HIV vaccine development using recombinant coxsackieviruses

描述(由申请人提供)：到目前为止，没有一种单一的疫苗策略能够引起被认为是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来创造重组疫苗，使用靶向表位策略，能够诱导不同的HIV特异性免疫反应。总体假设是，在适当的免疫学背景下，靶向HIV表位的表达将引发广泛的免疫反应。靶向表位策略的优点是在HIV疫苗中表达结构受限的、保守的免疫原肽将最大限度地减少逃逸突变的问题。拟议的研究与艾滋病毒疫苗有关，因为它描述了解决疫苗开发中两个关键问题的原则证明实验，即需要多样化的免疫反应和开发逃逸突变体。该建议的重点是：1)构建可诱导Gag p24特异性T辅助细胞反应的CVB4/HIV重组体；2)构建可诱导Gag p24特异性CTL反应的CVB4/HIV重组体；3)构建可诱导病毒中和抗体的CVB4/HIV重组体；4)评价经口服或鼻腔给药的CVB4/HIV重组体的免疫原性。T细胞增殖试验和ELISPOT试验将评估表达辅助性T细胞表位的重组体的免疫原性。表达CTL表位的重组体的免疫原性将用ELISPOT检测。表达B细胞表位的重组体的免疫原性将通过ELISA法和病毒中和试验进行评估。在每个类别中诱导最强免疫反应的重组体将被分组制成疫苗鸡尾酒。将对几种佐剂进行测试，以确定增强疫苗鸡尾酒诱导的艾滋病毒特异性免疫反应的广度和强度的佐剂。与公共卫生的相关性：迫切需要一种预防性疫苗来阻止艾滋病毒-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库和克服逃逸突变的问题。本提案描述了一种增强艾滋病毒特异性免疫反应并将逃逸突变问题降至最低的新方法。

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.