HIV vaccine development using recombinant coxsackieviruses

描述（由申请人提供）：迄今为止，没有一种单一的疫苗策略能够引起有效的艾滋病毒疫苗所必需的全部免疫反应。这项研究的长期目标是开发一个新的平台，利用靶向表位策略来制造重组疫苗，能够诱导多种hiv特异性免疫反应。总的假设是，在适当的免疫学背景下，靶向HIV表位的表达将引起广泛的免疫反应。靶向表位策略的优势在于，在HIV疫苗中表达结构受限的、保守的、免疫原性的肽，将最大限度地减少逃逸突变体的问题。拟议的研究与艾滋病毒疫苗有关，因为它描述了原则证明实验，以解决疫苗开发中的两个关键问题，即需要多样化的免疫反应和开发逃逸突变体。该方案的重点是：1)构建可诱导gag p24特异性T辅助细胞应答的CVB4/HIV重组体，2)构建可诱导gag p24特异性CTL应答的CVB4/HIV重组体，3)构建可诱导病毒中和抗体的CVB4/HIV重组体，以及4)评估经口服或鼻内给药的CVB4/HIV重组体鸡尾酒的免疫原性。表达T辅助细胞表位的重组体的免疫原性将通过T细胞增殖试验和ELISPOT试验进行评估。表达CTL表位的重组体的免疫原性将通过ELISPOT检测进行监测。表达B细胞表位的重组体的免疫原性将通过ELISA和病毒中和试验进行评估。在每种类型中诱导最强免疫反应的重组将被组合成一种鸡尾酒疫苗。将测试几种佐剂，以确定佐剂可以增强疫苗鸡尾酒诱导的hiv特异性免疫反应的广度和强度。与公共卫生的相关性：迫切需要一种预防性疫苗，以阻止艾滋病毒-1在全球的传播。目前的候选疫苗很有希望，因为它们能够诱导一些必要的免疫反应。需要新的疫苗策略来增加免疫反应的种类并克服逃逸突变体的问题。目前的建议描述了一种新的方法来增强艾滋病毒特异性免疫反应，并尽量减少逃逸突变体的问题。

DESCRIPTION (provided by applicant): To date, no single vaccine strategy is capable of eliciting the entire spectrum of immune responses deemed necessary for an effective HIV vaccine. The long-term goal of this study is to develop a new platform for creating recombinant vaccines, using a targeted epitope strategy, capable of inducing diverse HIV-specific immune responses. The overall hypothesis is that expression of targeted HIV epitopes, in appropriate immunological contexts, will elicit a wide range of immune responses. The advantage of a targeted epitope strategy is that expression of structurally constrained, conserved, immunogenic peptides in an HIV vaccine will minimize the problem of escape mutants. The proposed study is relevant for HIV vaccines because it describes proof-of-principle experiments to address two critical issues in vaccine development i.e. the need for diverse immune responses and the development of escape mutants. The proposal focuses on 1) Construction of CVB4/HIV recombinants that elicit gag p24-specific T helper cell responses, 2) Construction of a CVB4/HIV recombinant that elicits gag p24-specific CTL responses, 3) Construction of CVB4/HIV recombinants that elicit virus neutralizing antibodies, and 4) Evaluation of the immunogenicity of a cocktail of CVB4/HIV recombinants administered via the oral or intranasal route. The immunogenicity of recombinants expressing T helper cell epitopes will be evaluated using a T cell proliferation assay and the ELISPOT assay. The immunogenicity of recombinants expressing CTL epitopes will be monitored using the ELISPOT assay. The immunogenicity of recombinants expressing B cell epitopes will be assessed by ELISA and by a virus-neutralization assay. Recombinants that induce the strongest immune response in each category will be grouped to make a vaccine cocktail. Several adjuvants will be tested to identify adjuvants that enhance the breadth and strength of HIV-specific immune responses induced by the vaccine cocktail. Relevance to public health: A preventive vaccine is urgently needed to halt the global spread of HIV-1. Current vaccine candidates are promising in that they are able to induce some of the necessary immune responses. New vaccine strategies are needed to increase the repertoire of immune responses and to overcome the problem of escape mutants. The present proposal describes a new approach to augment HIV-specific immune responses and to minimize the problem of escape mutants.