Enhancing the Immunogenicity and Utility of MVA-Based AIDS Vaccines

描述（由申请人提供）：本提案的长期目标是开发安全有效的艾滋病疫苗。已经（或目前正在）在临床试验中评估了来自减毒痘病毒改良安卡拉牛痘病毒（MVA）的许多候选艾滋病疫苗。然而，许多因素限制了这些候选疫苗的免疫原性和实用性。这些包括由于与由载体编码的痘病毒蛋白的不利抗原竞争而导致的有限宽度的引发HIV特异性T细胞应答，以及在用重组MVA疫苗免疫后产生有效的抗载体免疫，其逐渐降低同源加强免疫以加强HIV特异性T和B细胞应答的有效性。因此，根据STEP试验结果，迫切需要发现新的病毒载体修饰和免疫策略，以最大限度地提高疫苗载体引起的HIV特异性T细胞应答的幅度、质量和广度。此外，艾滋病疫苗很可能需要产生广泛的中和抗体反应，除了CTL，才能发挥最大的作用。因此，必须确定用于呈递相关包膜抗原（一旦开发）的最佳载体和方法，以引发持久的高滴度中和抗体应答。为了实现这些目标，我们建议评估一些新的载体修饰，假设以增强基于MVA的艾滋病疫苗的细胞和体液免疫原性，并减轻预先存在的或免疫诱导的载体特异性免疫的负面影响。我们将追求以下具体目标：1）我们将检验这样的假设，即基于MVA的重组AIDS疫苗的免疫原性，特别是在表现出载体特异性免疫的宿主中的免疫原性，可以通过载体修饰而显著增强，所述载体修饰删除MVA特异性体液免疫的相关决定簇，并减弱补体中和病毒粒子感染性或促进体内MVA转导细胞的清除的能力; 2）我们将检验这样的假设，即由基于MVA的重组AIDS疫苗引起的HIV特异性T细胞和抗体应答的广度和幅度可以通过特异性靶向TLR-5介导的先天免疫信号传导途径的抗原刺激的载体修饰而显著增强。 公共卫生相关性：世界迫切需要艾滋病疫苗。我们建议开发新的基于改良安卡拉牛痘（MVA）的艾滋病疫苗，其免疫原性比来自MVA亲本菌株的载体更强。合理地改进MVA载体以引发更高水平的更高度多样化的HIV特异性T细胞和抗体应答，并减轻其对载体特异性中和抗体的诱导和敏感性，应导致新的候选艾滋病疫苗表现出比当前替代品更大的功效。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to develop a safe and efficacious AIDS vaccine. A number of candidate AIDS vaccines derived from the attenuated poxvirus Modified Vaccinia virus Ankara (MVA) have been (or currently are being) evaluated in clinical trials. However, a number of factors limit the immunogenicity and utility of these vaccine candidates. These include priming HIV-specific T cell responses that are of limited breadth, due to unfavorable antigenic competition with poxvirus proteins encoded by the vector, as well as the development of potent anti-vector immunity, following immunization with recombinant MVA vaccines, that progressively diminishes the effectiveness of homologous booster immunizations to boost HIV-specific T and B cell responses. As a result, and in light of the STEP trial results, there is an urgent need to discover new viral vector modifications and immunization strategies that maximize the magnitude, quality, and breadth of HIV-specific T cell responses that are elicited by vaccine vectors. In addition, it is quite likely that an AIDS vaccine will need to engender broadly neutralizing antibody responses, in addition to CTLs, to be maximally effective. As such, it is imperative to identify the best vectors and methodologies for presenting relevant envelope antigens (once developed) in order to elicit high-titer neutralizing antibody responses that are durable. Toward achieving these goals, we propose to evaluate a number of novel vector modifications that are hypothesized to enhance the cellular and humoral immunogenicity of MVA-based AIDS vaccines, and to mitigate the negative effects of pre-existing, or immunization-induced, vector-specific immunity. We will pursue the following specific aims: 1) We will test the hypothesis that the immunogenicity of recombinant MVA-based AIDS vaccines, particularly in hosts exhibiting vector-specific immunity, can be significantly enhanced through vector modifications that delete relevant determinants of MVA-specific humoral immunity and that attenuate the ability of complement to neutralize virion infectivity or to facilitate the clearance of MVA-transduced cells in vivo; 2) We will test the hypothesis that the breadth and magnitude of HIV-specific T cell and antibody responses that are elicited by recombinant MVA-based AIDS vaccines can be significantly enhanced through vector modifications that specifically target antigenic stimulation of TLR-5-mediated innate immune signaling pathways. PUBLIC HEALTH RELEVANCE: The world desperately needs an AIDS vaccine. We propose to develop novel Modified Vaccinia Ankara (MVA)-based AIDS vaccines that are more immunogenic than vectors derived from the parental strain of MVA. Rationally improving MVA vectors to elicit higher levels of more highly diverse HIV-specific T cell and antibody responses and to mitigate their induction of, and sensitivity to, vector-specific neutralizing antibodies, should result in new candidate AIDS vaccines that exhibit greater efficacy than current alternatives.