HIV Vaccines Targeting Glycan Epitopes: Improvement of a Vaccine Tested In IDUs

描述(由申请人提供)：这项工作的目标是开发一种安全、有效和负担得起的疫苗，以防止因注射毒品、无保护措施的性行为和接触污染的血液产品而导致的艾滋病毒-1感染。我们计划通过改进一种最初在注射吸毒者中测试的疫苗AIDSVAX B/E来实现这一目标。这项提议利用了最近的发现，表明HIV-1感染者血清中许多最有效的中和抗体是针对糖依赖的表位的。认识到广泛的中和抗体识别碳水化合物表位是革命性的，可能是艾滋病毒-1疫苗发展史上最伟大的进步之一。在这项提议中，我们计划利用这些信息来开发新的疫苗免疫原，由重组gp120和gp120片段(支架)组成，这些片段产生的糖基化是结合这些抗体所需的。我们计划使用这些免疫原来提高RV144和VAX003临床试验中使用的AIDSVAX B/E疫苗的疗效。我们最近的研究表明，这种疫苗缺乏产生针对这一新的重要表位的抗体所需的碳水化合物结构。这项建议成功的关键标准将是：1)识别免疫原和一种免疫方案，能够在实验室动物中诱导具有与原型PG9单抗相似的活性的广泛中和抗体，以及2)识别能够诱导与RV144试验中保护相关的V1/V2结构域抗体的免疫原。通过改进现有疫苗，并在15,000多名受试者中建立了安全和免疫原性的记录，现有的GMP制造工艺，并证明了有效性，我们相信，与从头开始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。这项建议将产生的其他有用信息包括：1)确定诱导抗gp120 V1/V2区糖依赖的抗体的最佳方法；2)确定gp120的V1和V2区新的糖依赖和独立的表位；3)了解针对V1/V2域的抗体反应的大小和特异性的差异，这些反应导致在RV144临床试验中获得保护，但在VAX003临床试验中无法保护注射吸毒者；以及4)了解由于免疫或病毒感染而产生gp120抗体的人中依赖糖的表位的抗体流行率。

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.