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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：拟议项目“引发广泛中和抗体的定向谱系免疫”使用 C 型免疫原（一系列逐步进化的 D/L 疫苗）来测试 HIV 疫苗接种的定向谱系 (D/L) 方法。 Env 免疫原用于驱动广泛中和抗体 (bnAb) 反应的发展，这很重要，因为它能够防止潜在储存库的建立和病毒持续存在。尚未实现这样的反应，但对自然感染人类的研究表明，在传播/创始人 (T/F) Env 刺激 bnAb 未突变共同祖先 (UCA) 的患者中，病毒和 B 的共同进化GeoVax 定向谱系疫苗旨在重现 Env 中的一系列突变，这些突变导致 bnAb 在经过充分研究的 C 分支感染患者中形成 CD4 结合位点 (CD4bs)。杜克大学CHAVI患者505。待测试的疫苗包括四种重组改良安卡拉痘苗病毒（rMVA）病毒疫苗，每种疫苗均表达非传染性病毒样颗粒（VLP），以及两种重组gp120蛋白疫苗。MVA表达的VLP在中展示Env。天然构象，而 gp120 能够有效增强 MVA 引发的抗体反应。疫苗将在生产中进行测试。恒河猴；使用恒河猴模型是必要的，因为 bnAb 的 UCA 的恒河猴种系序列与人类 UCA 是同源的。在 D/L 方案中，将用四种疫苗对动物进行免疫。从连续节点表达 Env 蛋白的不同 rMVA 疫苗，用于在患者 505 中引发针对 CD4b 的 bnAb；rMVA 免疫接种后将进行两次；使用与最进化的Env相对应的gp120疫苗进行免疫在T/F方案中，将用仅含有T/F序列的rMVA和gp120对动物进行免疫，在整个研究过程中，在设计的时间点从动物中采集血清样品。捕获峰值和收缩反应，将使用 ELISA 测试引发的结合抗体 (bAb) 和中和抗体 (nAb) 的强度、特异性和广度。我们的合作者 David Montefiori 博士将使用 gp120 和 gp160 抗原来证明免疫反应的总体强度和亚基特异性，并使用专门设计用于量化对 CD4 结合位点 (CD4bs) 的免疫反应的抗原。 nAb 测试将确定 nAb 反应的幅度和广度，并将确定引发的 nAb 的 CD4bs 特异性，GeoVax 还将测试引发的抗体的亲和力，这是 a 的潜在相关性。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发了 bnAb 反应，蛋白质增强是否增加了 bnAb 滴度，以及 D/L 方法是否相对于 T/L 方法改善了反应。如果 D/L 成功扩大了中和抗体反应，则临床试验将取得进展。如果 D/L 方法不能扩大 nAb 反应，则更简单的 T/F 疫苗将进入临床。。