Enhancing the Immunogenicity and Utility of MVA-Based AIDS Vaccines

描述(申请人提供)：这项建议的长期目标是开发一种安全有效的艾滋病疫苗。由减毒痘病毒修饰的安卡拉痘苗病毒(MVA)衍生的一些候选艾滋病疫苗已经(或目前正在)进行临床试验。然而，许多因素限制了这些候选疫苗的免疫原性和实用性。这些措施包括启动HIV特异性T细胞反应，由于与载体编码的痘病毒蛋白的不利抗原竞争，以及在重组MVA疫苗免疫后发展出强大的抗媒介免疫，这逐渐削弱了同源加强免疫以提高HIV特异性T细胞和B细胞反应的有效性。因此，根据分步试验的结果，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诱导的HIV特异性T细胞反应的数量、质量和广度。此外，除了CTL外，艾滋病疫苗很可能还需要产生广泛的中和抗体反应，才能发挥最大的效果。因此，必须确定呈现相关包膜抗原的最佳载体和方法(一旦开发)，以诱导持久的高滴度中和抗体反应。为了实现这些目标，我们建议评估一些新的载体修改，这些修改被假设为增强基于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媒介特异性免疫的负面影响。我们将追求以下特定目标：1)我们将测试基于MVA的重组艾滋病疫苗的免疫原性，特别是在表现出媒介特异性免疫的宿主中，可以通过载体修改显著增强免疫原性，这种修改删除了MVA特异性体液免疫的相关决定因素，并减弱了补体中和病毒粒子感染性的能力，或有助于体内MVA转导细胞的清除；2)我们将测试这样的假设，即通过针对TLR-5介导的天然免疫信号通路的抗原刺激的载体修改，可以显著增强MVA重组艾滋病疫苗诱导的HIV特异性T细胞和抗体反应的广度和幅度。 与公共卫生相关：世界迫切需要艾滋病疫苗。我们建议开发基于改良安卡拉疫苗(MVA)的新型艾滋病疫苗，这种疫苗比来自MVA亲本株的载体更具免疫原性。合理地改进MVA载体，以诱导更高水平的高度多样化的HIV特异性T细胞和抗体反应，并减轻它们对载体特异性中和抗体的诱导和敏感性，应该会导致新的候选艾滋病疫苗，比目前的替代疫苗显示出更好的效果。

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.