Design of HIV VLPs with Enhanced Immunogenicity

具有增强免疫原性的 HIV VLP 的设计

• 批准号: 7988855
• 负责人: RICHARD W COMPANS
• 金额: $ 49.72万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988855
• 关键词: AIDS prevention; Address; Adjuvant; Antibody Formation; Antigen Presentation; Antigens; Baculoviruses; Binding; CD8B1 gene; Cavia; Cells; Cellular Immunity; Code; DNA; DNA Vaccines; Data; Disease; Distal; Dose; Epitopes; Flagellin; GPI Membrane Anchors; Gagging; Generations; Genetic Variation; Glycoproteins; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; HIV-1 vaccine; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Incidence; Infection; Intramuscular; Leucine Zippers; Ligands; Mediating; Membrane; Modeling; Modification; Molecular; Mouse Mammary Tumor Virus; Mucosal Immune Responses; Mucous Membrane; Natural Immunity; Outcome; Particulate; Process; Proteins; Recombinants; Regimen; Reporting; Research; Route; SIV; Site; Structure; Surface; T-Lymphocyte; Testing; Toll-Like Receptor 5; Vaccination; Vaccines; Viral; Viral Antigens; Virion; Virus; Virus-like particle; base; cross reactivity; design; env Gene Products; gp160; immunogenic; immunogenicity; improved; influenzavirus; mouse model; mucosal site; neutralizing antibody; novel; novel strategies; novel virus; prophylactic; response; transmission process; vaccine development

DESCRIPTION (provided by applicant): A prophylactic HIV-1 vaccine is urgently needed, and an antigen that elicits strong broadly reactive neutralizing antibody (nAb) responses against the viral envelope glycoprotein would be an important component. However, the challenges in vaccine development include the extraordinary genetic diversity and immune evasion capacity of HIV-1 and the limited availability of epitopes for broadly nAbs. Immunogens that mimic an important process in natural infection and initiate appropriate innate immune responses are expected to be advantageous. Virus-like particles (VLPs) represent an attractive approach to present Env in a form similar to its exposure on virions. We recently reported that modified Env proteins can be designed to be incorporated into VLPs at very high levels (Wang, 2007). We hypothesize that VLPs containing such modified Env will elicit enhanced nAb responses, and are proposing additional new approaches to generate VLPs with greater immunogenicity. One approach will focus on enhancing the incorporation of stable Env trimers into VLPs. Alternatively, VLP immunogenicity will be enhanced by incorporation of molecular adjuvants, including a membrane -anchored form of flagellin, the natural ligand of the toll-like receptor 5 (TLR5), or a membrane- anchored form of GM-CSF. We expect that the resulting VLPs will elicit improved neutralizing antibody responses, as well as cell-mediated cellular immunity. We hypothesize that these novel VLPs will elicit higher titers of broadly reactive nAbs and enhanced mucosal immune responses when administered by mucosal inoculation, and we will test this hypothesis in a guinea pig model. Because DNA vaccines are effective in priming antibody responses as well as eliciting cellular responses (Singh et al., 2005), as a comparison we will also generate DNA constructs expressing clade B and C Env and Gag for use in priming by DNA vaccines, including a cross-clade DNA prime-VLP boost regimen to focus cross-clade immunity. Our goal is to develop an HIV vaccine that is effective at reducing the incidence of infection at mucosal surfaces. The combination of Env antigen presentation in its native state combined with a membrane-anchored adjuvant and mucosal delivery provides a promising approach to stimulate strong nAb response against HIV, designed to block the initial step in the infection process. Because of the relatively low efficiency of HIV transmission at mucosal surfaces, even a modest enhancement of protective mucosal responses could have a significant effect on reducing disease incidence. Among the possible outcomes which may result in such enhanced protection are: increasing the magnitude and/or duration of the response, increasing the breadth of cross-reactivity of the responses, and enhancing the levels of responses at local mucosal sites. Despite tremendous efforts, an effective vaccine for AIDS prevention remains elusive and novel approaches are needed. Our research is focused on developing novel particulate antigens that will elicit broadly reactive neutralizing antibody responses as well as cell-mediated immunity. We will also focus on enhancing immune responses at mucosal surfaces, where most HIV infections are transmitted.

描述（由申请人提供）： 迫切需要一种预防性HIV-1疫苗，并且一种针对病毒包膜糖蛋白产生强的广泛反应性中和抗体（nAb）应答的抗原将是一个重要组成部分。然而，疫苗开发的挑战包括HIV-1非凡的遗传多样性和免疫逃避能力以及广泛nAb表位的有限可用性。模拟自然感染中的重要过程并启动适当的先天免疫应答的免疫原预期是有利的。病毒样颗粒（VLP）代表了一种有吸引力的方法，以类似于其暴露在病毒体上的形式呈现Env。我们最近报道，修饰的Env蛋白可以被设计成以非常高的水平掺入VLP中（Wang，2007）。我们假设含有这种修饰的Env的VLP将引起增强的nAb应答，并提出了额外的新方法来产生具有更大免疫原性的VLP。一种方法将集中于增强稳定的Env三聚体掺入VLP中。或者，VLP免疫原性将通过掺入分子佐剂来增强，所述分子佐剂包括膜锚定形式的鞭毛蛋白、toll样受体5（TLR 5）的天然配体或膜锚定形式的GM-CSF。我们预期所得的VLP将引发改善的中和抗体应答，以及细胞介导的细胞免疫。我们假设这些新型VLP通过粘膜接种给药时将引发更高滴度的广泛反应性nAb和增强的粘膜免疫应答，我们将在豚鼠模型中检验这一假设。因为DNA疫苗在引发抗体应答以及引发细胞应答方面是有效的（Singh等人，2005），作为比较，我们还将产生表达进化枝B和C Env和Gag的DNA构建体，用于通过DNA疫苗引发，包括交叉进化枝DNA引发-VLP加强方案以集中交叉进化枝免疫。我们的目标是开发一种有效降低粘膜表面感染发生率的HIV疫苗。Env抗原在其天然状态下的呈递与膜锚定佐剂和粘膜递送的组合提供了一种有希望的方法来刺激针对HIV的强nAb应答，其设计用于阻断感染过程中的初始步骤。由于HIV在粘膜表面传播的效率相对较低，即使适度增强粘膜保护性反应也可能对降低疾病发病率产生显著影响。可能导致这种增强保护的可能结果包括：增加应答的幅度和/或持续时间，增加应答的交叉反应性的广度，以及增强局部粘膜部位的应答水平。尽管作出了巨大努力，但预防艾滋病的有效疫苗仍然难以捉摸，需要新的方法。我们的研究重点是开发新的颗粒抗原，这将引起广泛的反应性中和抗体反应以及细胞介导的免疫。我们还将专注于增强粘膜表面的免疫反应，大多数HIV感染都是在粘膜表面传播的。