Enhancing the Immunogenicity and Utility of MVA-Based AIDS Vaccines

增强基于 MVA 的艾滋病疫苗的免疫原性和实用性

• 批准号: 8075652
• 负责人: John David Altman
• 金额: --
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8075652
• 关键词: AIDS Vaccines; AIDS vaccine development; Acquired Immunodeficiency Syndrome; Adenoviruses; Agonist; Antibodies; Antibody Formation; Antigen Targeting; Antigenic Diversity; Antigens; Attenuated; B-Lymphocytes; Cells; Chimeric Proteins; Clinical; Clinical Trials; Complement; Complement Activation; Complement Inactivators; Dendritic Cells; Development; Effectiveness; Enzymes; Epitopes; Exhibits; Flagellin; Funding; Future; Generations; Goals; HIV; HIV Antigens; HIV-1; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Infection; Light; Link; Longevity; Mediating; Membrane Proteins; Methodology; Modification; Modified Vaccinia Virus Ankara; Mus; National Institute of Allergy and Infectious Disease; Poxviridae; Proteins; Recombinants; Research; Secondary Immunization; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Smallpox; Surface; System; T cell response; T-Lymphocyte; Testing; Vaccines; Vaccinia; Vaccinium; Viral Vaccines; Viral Vector; Virion; Virus; base; cellular transduction; efficacy trial; env Gene Products; experience; immunogenic; immunogenicity; improved; in vivo; innovation; neutralizing antibody; novel; novel strategies; pandemic disease; pre-clinical; premature; programs; public health relevance; research clinical testing; response; vaccine candidate; vaccine efficacy; vector; vector vaccine; vector-based vaccine; vector-induced

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.

描述（由申请人提供）：该提案的长期目标是开发一种安全有效的艾滋病疫苗。许多源自减毒痘病毒、改良痘苗病毒安卡拉 (MVA) 的候选艾滋病疫苗已经（或目前正在）进行临床试验评估。然而，许多因素限制了这些候选疫苗的免疫原性和实用性。这些包括由于与载体编码的痘病毒蛋白的不利抗原竞争而引发广度有限的HIV特异性T细胞反应，以及在用重组MVA疫苗免疫后产生有效的抗载体免疫力，这种免疫力逐渐减弱同源加强免疫增强 HIV 特异性 T 和 B 细胞反应的有效性。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发的 HIV 特异性 T 细胞反应的程度、质量和广度。此外，除了 CTL 之外，艾滋病疫苗很可能还需要产生广泛的中和抗体反应，才能发挥最大效果。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反应。为了实现这些目标，我们建议评估一些新的载体修饰，这些修饰被假设可以增强基于 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的负面影响。特异性免疫。我们将追求以下具体目标：1）我们将测试以下假设：通过删除 MVA 特异性相关决定因素的载体修饰，可以显着增强基于 MVA 的重组艾滋病疫苗的免疫原性，特别是在表现出载体特异性免疫的宿主中。体液免疫并减弱补体中和病毒粒子感染性或促进体内 MVA 转导细胞清除的能力； 2) 我们将检验以下假设：通过特异性针对 TLR-5 介导的先天性抗原刺激的载体修饰，可以显着增强基于重组 MVA 的艾滋病疫苗引发的 HIV 特异性 T 细胞和抗体反应的广度和程度。免疫信号通路。 公共卫生相关性：世界迫切需要艾滋病疫苗。我们建议开发新型安卡拉改良牛痘 (MVA) 艾滋病疫苗，该疫苗比源自 MVA 亲本株的载体更具免疫原性。合理改进 MVA 载体以引发更高水平、更高度多样化的 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，应该会产生比现有艾滋病疫苗更有效的新候选艾滋病疫苗替代方案。