Mature virus-like particles as a new strategy for dengue virus vaccines

成熟的病毒样颗粒作为登革热病毒疫苗的新策略

• 批准号: 8675180
• 负责人: Wei-Kung Wang
• 金额: $ 30.35万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675180
• 关键词: Accounting; Antibodies; Antibody-Dependent Enhancement; Attenuated; Avidity; Binding; Categories; DNA Vaccines; Dengue; Dengue Virus; Disease; E protein; Enhancing Antibodies; Epitopes; Equilibrium; Generations; Goals; Human; Immune response; Infection; Interferon Receptor; Life; Measures; Mediating; Membrane; Modeling; Mono-S; Monoclonal Antibodies; Mus; Peptides; Reporting; Research; Rest; Risk; Serotyping; Serum; Specificity; Standard Preparations; T cell response; Testing; Translating; Vaccine Design; Vaccines; Viral Load result; Virion; Virus Diseases; Virus-like particle; arbovirus disease; base; neutralizing antibody; neutralizing monoclonal antibodies; novel strategies; particle; public health relevance; response; vaccine candidate

DESCRIPTION (provided by applicant): Despite considerable effort and progress in developing tetravalent vaccines against the four serotypes of dengue virus (DENV), one of the major unmet challenges is the difficulty in eliciting balanced neutralizing (NT) antibodies (Abs) against all four serotypes and to lower the risk of antibody-dependent enhancement (ADE), mediated mainly by cross-reactive and weakly or non-NT Abs. Studies of human Abs after DENV infection have shown the immunodominance of cross-reactive and weakly or non-NT Abs recognizing the fusion loop (FL) of envelope (E) protein over the type-specific and potent NT Abs, and the presence of cross-reactive and weakly or non-NT anti-precursor membrane (prM) Abs. Whether such immunodominance can be modulated to induce potent NT Abs without cross-reactive and weakly or non-NT Abs remains unknown. We recently found a DNA vaccine expressing mature DENV particles induced potent NT Abs with minimal cross-reactive, weakly or non-NT Abs, suggesting that specific modulation of DENV particles might induce superior Ab responses. Our long-term goal is to develop a safe and effective DENV vaccine. The objective of the proposed research is to understand the immunodominance of DENV E protein and to test whether mature or FL-modified mature DENV particles can induce potent NT Abs without cross-reactive, weakly or non-NT Abs. The central hypothesis is that mature DENV particles induce potent NT Abs, less anti-FL Abs and no anti-prM Abs, thus reducing the risk of ADE compared with mixed DENV particles. The objective will be achieved by the three specific aims: The first specific aim is to define the E protein epitopes and the accessibility, binding avidity and NT potency of a large panel of anti-E mAbs on mature, mixed and immature DENV particles. We hypothesize that differential epitope accessibility and binding avidity of anti-E Abs to different DENV particles may account for the immunodominance of E protein. The second aim is to demonstrate the superiority of DNA vaccines expressing mature DENV particles, over DNA vaccines expressing mixed particles, in eliciting potent NT Abs and minimal potential enhancing Abs and providing protection in outbred mice and AG129 mice, a well-established dengue murine model. The third aim is to demonstrate the superiority of DNA vaccines expressing FL-modified mature DENV particles, over DNA vaccines expressing non-modified mature DENV particles, in eliciting potent NT Abs and minimal potential enhancing Abs and providing protection in murine models. The significance of the proposed research rests on its detailed understanding of the immunodominance of DENV E protein and on the demonstration that such immunodominance can be modulated by mature and FL-modified DENV particles to induce potent NT Abs and minimal infection-enhancing Abs. This represents a novel strategy for DENV vaccine design and cannot be achieved by all current DENV particle-based candidate vaccines. The proposed research can be translated to several more advanced DENV vaccine candidates as the second generation of "safe and effective" DENV vaccines.

描述（由申请人提供）：尽管在开发针对登革热病毒（DENV）四种血清型的四价疫苗方面付出了相当大的努力并取得了进展，但尚未解决的主要挑战之一是难以引发针对所有四种血清型的平衡中和（NT）抗体（Abs）血清型并降低主要由交叉反应性和弱或非 NT Ab 介导的抗体依赖性增强 (ADE) 的风险。 DENV 感染后对人类抗体的研究表明，识别包膜 (E) 蛋白融合环 (FL) 的交叉反应性弱或非 NT 抗体相对于类型特异性和强效 NT 抗体具有免疫优势，并且交叉反应性抗体的存在-反应性弱或非 NT 抗前体膜 (prM) 抗体。是否可以调节这种免疫优势来诱导有效的 NT 抗体而不产生交叉反应以及弱或非 NT 抗体仍然未知。我们最近发现了一种表达成熟 DENV 颗粒的 DNA 疫苗，可诱导有效的 NT 抗体，同时具有最小的交叉反应、弱或非 NT 抗体，这表明 DENV 颗粒的特定调节可能会诱导优异的抗体反应。 我们的长期目标是开发安全有效的登革热病毒疫苗。本研究的目的是了解 DENV E 蛋白的免疫优势，并测试成熟或 FL 修饰的成熟 DENV 颗粒是否可以诱导有效的 NT 抗体，而不会产生交叉反应、弱或非 NT 抗体。核心假设是，成熟的 DENV 颗粒诱导有效的 NT 抗体、较少的抗 FL 抗体且没有抗 prM 抗体，从而与混合 DENV 颗粒相比降低了 ADE 风险。该目标将通过三个具体目标来实现：第一个具体目标是确定 E 蛋白表位以及大量抗 E 单克隆抗体在成熟、混合和未成熟 DENV 颗粒上的可及性、结合亲合力和 NT 效力。我们假设抗 E 抗体与不同 DENV 颗粒的不同表位可及性和结合亲和力可能解释了 E 蛋白的免疫优势。第二个目标是证明表达成熟 DENV 颗粒的 DNA 疫苗相对于表达混合颗粒的 DNA 疫苗在引发有效 NT 抗体和最小潜在增强抗体方面的优越性，并为近交系小鼠和 AG129 小鼠（一种成熟的登革热小鼠模型）提供保护。 。第三个目标是证明表达 FL 修饰的成熟 DENV 颗粒的 DNA 疫苗相对于表达未修饰的成熟 DENV 颗粒的 DNA 疫苗在引发有效 NT 抗体和最小潜力增强抗体以及在小鼠模型中提供保护方面具有优越性。 本研究的意义在于详细了解 DENV E 蛋白的免疫优势，并证明这种免疫优势可以通过成熟和 FL 修饰的 DENV 颗粒进行调节，以诱导有效的 NT 抗体和最小的感染增强抗体。这代表了一种新的 DENV 疫苗设计策略，目前所有基于 DENV 颗粒的候选疫苗都无法实现。拟议的研究可以转化为几种更先进的 DENV 候选疫苗，作为第二代“安全有效”的 DENV 疫苗。