Re-engineering gp120 to include glycan-dependent epitopes

重新设计 gp120 以包含聚糖依赖性表位

基本信息

批准号：
8777908
负责人：
Phillip Wayne Berman
金额：
$ 202.62万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-18 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8777908
关键词：
Africa Antibodies Antibody Affinity Antibody Formation Antigens Attention Basic Science Binding Biochemical Biological Assay Carbohydrates Cell Culture System Cell Line Cells Chinese Hamster Ovary Cell Circular Dichroism Clinical Clinical Trials Complex Data Development Engineering Ensure Epitopes Equipment Follow-Up Studies Goals HIV HIV Envelope Protein gp120 HIV vaccine HIV-1 Heterogeneity Human Immunization Individual Infection Injecting drug user Laboratory Animals Mass Spectrum Analysis Methods Monoclonal Antibodies Mus National Institute of Allergy and Infectious Disease Normal Cell Oryctolagus cuniculus Phase III Clinical Trials Polysaccharides Populations at Risk Prevalence Production Proteins Proteolysis Protocols documentation Qualifying Recombinants Recording of previous events Regimen Research Resistance Safety Serum Specificity Structure Subunit Vaccines Testing Thailand Time Unsafe Sex Vaccine Antigen Vaccine Research Vaccines Virus Virus Diseases Work analytical method blood product carbohydrate structure clinical material cost env Gene Products experience follow-up glycosylation immunogenicity improved injection drug use kifunensine manufacturing process neutralizing antibody nonhuman primate novel novel vaccines pre-clinical prevent process optimization public health relevance scaffold scale up skills stability testing success synthetic peptide vaccine development

项目摘要

DESCRIPTION (provided by applicant): The goal of this work is the development of a safe, effective, and affordable vaccine to prevent HIV-1 infection resulting from injection drug use, unprotected sex, and exposure-contaminated blood products. We plan to accomplish this goal by improving a vaccine originally tested in injection drug users, AIDSVAX B/E. This proposal takes advantage of recent discoveries demonstrating that many of the most potent neutralizing antibodies in sera from HIV-1-infected people are directed to glycan-dependent epitopes. The recognition that broadly neutralizing antibodies recognize carbohydrate epitopes is revolutionary, and represents perhaps one of the greatest advances in the history of HIV-1 vaccine development. In this proposal, we plan to use this information to develop new vaccine immunogens consisting of recombinant gp120 and fragments of gp120 (scaffolds) produced with the glycosylation required for the binding of these antibodies. We plan to use these immunogens to improve the efficacy of the AIDSVAX B/E vaccine used in the RV144 and VAX003 clinical trials. Our recent studies showed that this vaccine lacked the carbohydrate structure required for the production of antibodies to this new and important class of epitopes. The key criteria of success in this proposal will be: 1) the identification of immunogens and an immunization regimen able to elicit broadly neutralizing antibodies in laboratory animals with activity similar to the prototypic PG9 monoclonal antibody, and 2) the identification of immunogens able to elicit antibodies to the V1/V2 domain of the type that correlated with protection in the RV144 trial. By improving an existing vaccine with an established record of safety and immunogenicity in more than 15,000 subjects, an existing GMP manufacturing process, and demonstrated efficacy, we believe that years of time and millions of dollars can be saved, compared with the cost of developing a new vaccine from scratch. Other useful information that will result from this proposal includes: 1) determining the best method to elicit antibodies to glycan-dependent epitopes in the V1/V2 domain of gp120; 2) the identification of new glycan-dependent and -independent epitopes in the V1 and V2 domains of gp120; 3) understanding the differences in the magnitude and specificity of antibody responses to V1/V2 domain that led to protection in the RV144 clinical trial and was unable to protect injection drug users in the VAX003 clinical trial, and 4) understanding the prevalence of antibodies to glycan dependent epitopes in people who make antibodies to gp120 as a consequence of immunization or virus infection.

描述（由申请人提供）：这项工作的目标是开发一种安全、有效且负担得起的疫苗，以预防因注射吸毒、无保护性行为和暴露污染的血液制品而导致的 HIV-1 感染。我们计划通过改进最初在注射吸毒者中测试的疫苗 AIDSVAX B/E 来实现这一目标。该提案利用了最近的发现，证明 HIV-1 感染者血清中许多最有效的中和抗体都针对聚糖依赖性表位。广泛中和抗体识别碳水化合物表位的认识是革命性的，并且可能代表了 HIV-1 疫苗开发史上最伟大的进步之一。在本提案中，我们计划利用这些信息来开发新的疫苗免疫原，其中包含重组 gp120 和 gp120 片段（支架），这些片段是通过这些抗体结合所需的糖基化产生的。我们计划利用这些免疫原来提高RV144和VAX003临床试验中使用的AIDSVAX B/E疫苗的功效。我们最近的研究表明，这种疫苗缺乏产生针对这一类新的重要表位的抗体所需的碳水化合物结构。该提案成功的关键标准是：1) 鉴定出免疫原和免疫方案，能够在实验动物中引发广泛中和抗体，其活性与原型 PG9 单克隆抗体相似，2) 鉴定出能够引发广泛中和抗体的免疫原。与 RV144 试验中的保护相关的类型的 V1/V2 结构域抗体。我们相信，通过改进现有的疫苗（在超过 15,000 名受试者中具有安全性和免疫原性记录）、现有的 GMP 生产工艺以及已证明的功效，与开发新疫苗的成本相比，可以节省数年的时间和数百万美元。新疫苗从头开始。该提案产生的其他有用信息包括：1) 确定诱导针对 gp120 V1/V2 结构域中聚糖依赖性表位的抗体的最佳方法； 2) gp120 V1 和 V2 结构域中新的聚糖依赖性和非依赖性表位的鉴定； 3) 了解对 V1/V2 结构域的抗体反应的幅度和特异性的差异，这些差异在 RV144 临床试验中提供了保护，但在 VAX003 临床试验中无法保护注射吸毒者，以及 4) 了解抗体的流行情况由于免疫或病毒感染而产生 gp120 抗体的人体内的聚糖依赖性表位。