Directed Lineage Immunizations for Eliciting Broadly Neutralizing Antibody

用于引发广泛中和抗体的定向谱系免疫

• 批准号: 8993072
• 负责人: Arban Domi
• 金额: $ 29.96万
• 依托单位: GEOVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8993072
• 关键词: AIDS prevention; Address; Adjuvant; Animal Testing; Animals; Antibodies; Antibody Diversity; Antibody Formation; Antibody Response; Antigens; Archives; Autopsy; Avidity; B-Lymphocytes; Binding; Binding Sites; Biological Assay; Budgets; C-terminal; CCR5 gene; CD8B1 gene; Cells; Characteristics; Clinic; Clinical Trials; Contracts; Data Analyses; Development; Evolution; Experimental Models; Generations; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; Harvest; Human; IgG3; Immune response; Immune system; Immunization; Immunodominant Epitopes; Immunoglobulin A; Infection; Laboratories; Lead; Length; Macaca mulatta; Modeling; Modified Vaccinia Virus Ankara; Molecular Conformation; Mosses; Mutation; Patients; Personal Communication; Persons; Phase; Production; Proteins; Recombinant Proteins; Recombinants; Regimen; Relative (related person); Sampling; Series; Serum; Small Business Innovation Research Grant; Somatic Mutation; Specificity; Surface; Swab; T-Lymphocyte; Testing; Time; Vaccination; Vaccine Design; Vaccines; Viral; Viral Vaccines; Virus; Virus-like particle; aluminum sulfate; antibody-dependent cell cytotoxicity; complementarity-determining region 3; design; env Gene Products; experience; gp160; immunogenicity; improved; innovation; neutralizing antibody; novel vaccines; pre-clinical; prevent; public health relevance; recombinant virus vaccine; research clinical testing; response; success; transmission process; vaccine development

 DESCRIPTION (provided by applicant): The proposed project, Directed Lineage Immunizations for Eliciting Broadly Neutralizing Antibody, tests the directed lineage (D/L) approach to HIV vaccination using clade C immunogens. With a D/L vaccine, a series of progressively evolved Env immunogens are used to drive development of a broadly neutralizing antibody (bnAb) response, which is important because of its ability to prevent the establishment of latent reservoirs and viral persistence. No vaccine has yet achieved such a response, but studies of naturally infected humans have shown that in patients in whom a transmitted/founder (T/F) Env has stimulated an unmutated common ancestor (UCA) for bnAb, the co-evolution of virus and B cells can lead to somatic mutations that generate bnAb. The GeoVax directed lineage vaccine is designed to reproduce the series of mutations in Env that led to development of bnAb to the CD4 binding site (CD4bs) in one well studied clade C infected patient, Duke CHAVI patient 505. The vaccines to be tested include four recombinant Modified Vaccinia Ankara (rMVA) viral vaccines, each expressing non-infectious Virus-Like Particles (VLP), and two recombinant gp120 protein vaccines. The MVA-expressed VLPs display Env in a native conformation, while the gp120s are potent at boosting MVA-elicited Ab responses. The vaccines will be produced and then tested in rhesus macaques; use of the rhesus model is essential because the rhesus germline sequence for the UCA for bnAb to the CD4bs is orthologous to the human UCA. Two different regimens will be tested. In the D/L regimen, animals will be immunized with four different rMVA vaccines expressing Env proteins from sequential nodes for the elicitation of bnAb to the CD4bs in patient 505; the rMVA immunizations will be followed by two immunizations with gp120 vaccine corresponding to the most evolved Env. In the T/F regimen, animals will be immunized with rMVAs and gp120s containing only the T/F sequence. Serum samples will be taken from the animals throughout the study, at time points designed to capture peak and contracted responses. The sera will be tested for magnitude, specificity, and breadth of elicited binding antibody (bAb) and neutralizing antibody (nAb). ELISAs will be performed with gp120 and gp160 antigens to demonstrate the overall magnitude and subunit specificity of the immune response and also with antigens specifically designed to quantify immune responses to the CD4 binding site (CD4bs). Testing for nAb will be performed by our collaborator, Dr. David Montefiori. The nAb testing will determine the magnitude and breadth of the nAb response and will determine the CD4bs specificity of elicited nAb. GeoVax will also test elicited Ab for avidity, a potential correlate of protection. Analysis of the data will allow GeoVa to characterize the immune responses and to determine whether the new vaccine design successfully elicited a bnAb response, whether the protein boost increased bnAb titer, and whether the D/L approach improved responses relative to the T/F immunizations. If the D/L is successful at broadening the neutralizing Ab response, it will be advance in clinical testing. If te D/L approach does not broaden the nAb response, the simpler T/F vaccine will be advanced into the clinic.

 描述（由适用提供）：拟议的项目，用于引发广泛中和抗体的定向谱系免疫接种，使用进枝C免疫来测试针对HIV疫苗的定向谱系（D/L）方法。使用D/L疫苗，一系列逐渐进化的ENV免疫原被用来驱动广泛中和抗体（BNAB）反应的发展，这很重要，因为它具有防止建立潜在储备和病毒持续性的能力。尚无疫苗能够达到这种反应，但是对自然感染的人类的研究表明，在传播/创始人（T/F）ENV的患者中，刺激了BNAB的未经分泌的共同祖先（UCA），病毒和B细胞的共同进化可以导致产生BNAB的体细胞突变。指导的谱系疫苗旨在重现ENV中的一系列突变，这些突变导致在一个井井有条的进化枝C感染患者中，导致BNAB开发到CD4结合位点（CD4B）（CD4BS）。 （VLP）和两种重组GP120蛋白疫苗。 MVA表达的VLP以天然构型显示ENV，而GP120的潜力在增强MVA引诱的AB响应方面具有潜力。疫苗将在恒河猕猴中生产然后测试；使用恒河猴模型是必不可少的，因为BNAB的UCA的恒河类系序对CD4BS是人类UCA的直系同源。将测试两种不同的方案。在D/L方案中，将用四种不同的RMVA疫苗对动物进行免疫，这些疫苗从顺序淋巴结中表达ENV蛋白，以促进BNAB，以在患者505中向CD4BS诱导。 RMVA免疫将进行两种免疫抑制，其GP120疫苗对应于最进化的Env。在T/F方案中，将仅包含T/F序列的RMVA和GP120对动物进行免疫。在整个研究中，在旨在捕获峰值和收缩反应的时间点上，将从动物中获取血清样品。血清将测试引起结合抗体（BAB）和中和抗体（NAB）的大小，特异性和广度。 ELISA将使用GP120和GP160抗原进行，以证明免疫响应的整体幅度和亚基特异性以及专门设计的抗原旨在将免疫调查量化为CD4结合位点（CD4BS）。 NAB的测试将由我们的合作者David Montefiori博士进行。 NAB测试将确定NAB响应的大小和广度，并确定引起的NAB的CD4BS特异性。 Geovax还将测试敏感的AB是否有生动，这是一个潜在的保护相关性。对数据的分析将使GEOVA能够表征免疫反应，并确定新的疫苗设计是否成功引起了BNAB反应，蛋白质的增强是否增加了BNAB滴度，以及相对于T/F免疫抑制的D/L方法是否改善了反应。如果D/L在扩大中和AB反应方面取得了成功，则将在临床测试中进行进步。如果TE D/L方法没有扩大NAB响应，则将较简单的T/F疫苗进入诊所。