HIV vaccine development using recombinant coxsackieviruses

描述（由申请方提供）：迄今为止，没有一种疫苗策略能够引发有效HIV疫苗所需的整个免疫应答谱。这项研究的长期目标是开发一个新的平台，用于创建重组疫苗，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应答。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、免疫原性肽将使逃逸突变体的问题最小化。拟议的研究与艾滋病毒疫苗有关，因为它描述了原理验证实验，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逃逸突变体的发展。该提案的重点是1）构建可引发gag p24特异性T辅助细胞应答的CVB 4/HIV重组体，2）构建可引发gag p24特异性CTL应答的CVB 4/HIV重组体，3）构建可引发病毒中和抗体的CVB 4/HIV重组体，以及4）评价通过口服或鼻内途径给予的CVB 4/HIV重组体混合物的免疫原性。表达T辅助细胞表位的重组体的免疫原性将使用T细胞增殖测定和ELISPOT测定进行评价。表达CTL表位的重组体的免疫原性将使用ELISPOT测定来监测。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。在每个类别中诱导最强免疫应答的疫苗将被分组以制备疫苗鸡尾酒。将对几种佐剂进行测试，以确定增强由疫苗混合物诱导的HIV特异性免疫应答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HIV-1的全球传播。目前的候选疫苗是有希望的，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应答的库并克服逃逸突变体的问题。本提案描述了一种新的方法，以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.