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: 9036322
• 负责人: Wei-Kung Wang
• 金额: $ 30.75万
• 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/9036322
• 关键词: Accounting; Antibodies; Antibody Formation; Antibody-Dependent Enhancement; Attenuated; Avidity; Binding; Categories; DNA Vaccines; Dengue; Dengue Infection; Dengue Virus; Disease; E protein; Enhancing Antibodies; Epitopes; Equilibrium; Generations; Goals; Health; Human; Immune response; Infection; Interferon Receptor; Life; Measures; Mediating; Membrane; 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-like particle; arbovirus disease; base; mouse model; neutralizing antibody; neutralizing monoclonal antibodies; novel strategies; particle; 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病毒（DENV）的四种血清型的四价疫苗方面做出了相当大的努力和进展，但主要未解决的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（Ab），以及难以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。对DENV感染后的人Ab的研究表明，识别包膜（E）蛋白的融合环（FL）的交叉反应性和弱或非NT Ab的免疫优势超过类型特异性和有效的NT Ab，以及交叉反应性和弱或非NT抗前体膜（prM）Ab的存在。这种免疫优势是否可以被调节以诱导有效的NT抗体而没有交叉反应性和弱或非NT抗体仍然是未知的。我们最近发现表达成熟DENV颗粒的DNA疫苗诱导了具有最小交叉反应性、弱或非NT Ab的有效NT Ab，表明DENV颗粒的特异性调节可能诱导上级Ab应答。 我们的长期目标是开发安全有效的DENV疫苗。所提出的研究的目的是了解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 Ab而没有交叉反应性、弱或非NT Ab。中心假设是成熟的DENV颗粒诱导有效的NT Ab，较少的抗FL Ab和无抗prM Ab，因此与混合的DENV颗粒相比降低了ADE的风险。该目标将通过三个具体目标来实现：第一个具体目标是定义E蛋白表位以及一大组抗E mAb对成熟、混合和未成熟DENV颗粒的可及性、结合亲合力和NT效力。我们推测，不同的抗原表位的可及性和不同的DENV颗粒的抗E抗体的结合亲合力可能占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疫苗相对于表达混合颗粒的DNA疫苗在引发有效NT Ab和最小潜在增强Ab以及在远交小鼠和AG129小鼠（一种良好建立的登革热鼠模型）中提供保护方面的优越性。第三个目的是证明表达FL修饰的成熟DENV颗粒的DNA疫苗在诱导有效的NT Ab和最小的潜在增强Ab以及在鼠模型中提供保护方面优于表达未修饰的成熟DENV颗粒的DNA疫苗。 该研究的意义在于其对DENV E蛋白免疫显性的详细理解，以及证明这种免疫显性可以通过成熟和FL修饰的DENV颗粒来调节，以诱导有效的NT抗体和最小的感染增强抗体。这代表了DENV疫苗设计的新策略，并且不能通过所有当前基于DENV颗粒的候选疫苗实现。这项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。