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）：尽管巨大的努力和进步在开发针对登革热病毒（DENV）的四种血清型的四个疫苗方面的进展，但主要的未满足挑战之一是在引起均衡中和（NT）抗体（ABS）抗体（ABS）对所有四种抗体和较低抗体的风险（不依赖于抗体）的风险（不依赖于抗体），而不是依赖于抗体的风险，而不是依赖于抗体（ABS），而不是依赖于抗体的风险（腹肌。 DENV感染后的人类ABS的研究表明，交叉反应性，弱或非NT ABS的免疫措施在类型特异性且有效的NT ABS上识别融合环（E）蛋白的融合环（fl），以及交叉反应性和弱反应性和弱或非NT抗抗抗物体膜（PRM）（PRM）abs的存在。是否可以调节这种免疫主导地诱导有效的NT ABS，而无需交叉反应，弱或非NT ABS仍然未知。最近，我们发现一种表达成熟DENV颗粒的DNA疫苗诱导有效的NT ABS，具有最小的交叉反应，弱或非NT ABS，这表明DENV颗粒的特定调节可能会诱导出色的AB反应。 我们的长期目标是开发安全有效的DENV疫苗。拟议的研究的目的是了解DENV E蛋白的免疫降低性，并测试成熟还是FL修饰的成熟DENV颗粒是否可以诱导有效的NT ABS，而无需交叉反应，弱或非NT ABS。中心假设是成熟的DENV颗粒会诱导有效的NT ABS，较少的抗FL ABS和无抗PRM ABS，从而降低了与混合DENV颗粒相比的ADE风险。该目标将通过三个特定目的来实现：第一个具体目的是定义E蛋白表位以及一大型抗E mAb在成熟，混合和未成熟的DENV颗粒上的可访问性，结合伴随和NT效力。我们假设抗E ABS与不同DENV颗粒的差异表位可及性和结合伴侣可能造成E蛋白的免疫优势。第二个目的是证明表达成熟DENV颗粒的DNA疫苗比表达混合颗粒的DNA疫苗的优越性，在引起有效的NT ABS和最小电势增强的ABS并提供了AGBRED小鼠和AG129小鼠的保护方面，这是一种已建立的登革热鼠模型。第三个目的是证明表达FL修饰成熟DENV颗粒的DNA疫苗比表达非改性成熟DENV颗粒的DNA疫苗的优越性，在引起有效的NT ABS和最小的潜在势能增强ABS并在鼠模型中提供保护方面的优势。 拟议的研究的重要性取决于其对DENVE蛋白免疫官方的详细理解，并证明了这种免疫主导性可以通过成熟和FL修饰的DENV颗粒调节，以诱导有效的NT ABS和最小的感染增强的ABS。这代表了DENV疫苗设计的一种新型策略，所有当前基于DENV粒子的候选疫苗无法实现。拟议的研究可以转化为几种更先进的DENV疫苗候选物，为第二代“安全有效” DENV疫苗。