PRECLINICAL ASSAYS TO PREDICT TETRAVALENT DENGUE VACCINE EFFICACY

预测四价登革热疫苗功效的临床前测定

• 批准号: 9901414
• 负责人: Aravinda M. DeSilva
• 金额: $ 107.57万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-08 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901414
• 关键词: 3-Dimensional; Antibodies; Antibody Response; Archives; Asia; Attenuated; Biological Assay; Biomimetics; Blocking Antibodies; Cell Culture Techniques; Clinical Trials; Collaborations; Complex; Culicidae; Dengue; Dengue Fever; Dengue Infection; Dengue Vaccine; Dengue Virus; Development; Disease; Epitopes; Evaluation; Exposure to; Formulation; Goals; Human; Immune; Immunity; Immunology procedure; Individual; Infection; Laboratories; Latin America; Link; Measures; Modeling; North Carolina; Pathogenicity; Performance; Peripheral; Phase; Population; Positioning Attribute; Pre-Clinical Model; Property; Reagent; Recombinants; Reporting; Research; Research Personnel; Sampling; Serotyping; Serum; Site; Specificity; Standardization; Structure; Testing; Time; Tissues; Universities; Vaccinated; Vaccination; Vaccines; Viral; Virion; Virus; Virus Diseases; Yellow Fever; arthropod-borne; base; diagnostic assay; efficacy study; efficacy trial; experience; human disease; human monoclonal antibodies; in vivo; neutralizing antibody; novel; pre-clinical; preclinical evaluation; prevent; programs; research clinical testing; response; transmission process; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation

Program Summary Dengue is the most common arthropod borne viral disease of humans. Vaccines are urgently needed to prevent dengue yet vaccine development is complicated by the presence of four dengue virus (DENV) serotypes and the possibility of immune enhanced dengue disease. The leading vaccine candidates contain 4 live attenuated viruses to cover the 4 serotypes. The most advanced vaccine candidate, a chimeric Yellow Fever-Dengue tetravalent live virus vaccine (CYD-TDV) developed by Sanofi Pasteur, was recently evaluated in human efficacy studies conducted in Asia and Latin America. Overall, CYD-TDV was efficacious at reducing the burden of dengue disease in the vaccinated populations. However, the vaccine had unexpectedly low efficacy against DENV serotype 2 (DENV2) and in dengue naïve subjects compared to dengue exposed subjects who were vaccinated. The lower efficacy in these groups was unexpected because the vaccine induced neutralizing antibodies (Abs) in these subjects. The central hypothesis of this proposal is that the quality (Ab epitope specificity) rather than total quantity of cell-culture neutralizing Abs is a better predictor of DENV vaccine performance in human populations. Moreover, as the DENV complex has 4 serotypes and vaccines will be used in populations with a mix of naïve and partially immune individuals, immune assays based on a single epitope are unlikely to predict efficacy against the 4 serotypes. This project is grounded on studies in our laboratories to understand protective and pathogenic Ab responses in people exposed to natural DENV infections. We have discovered new quaternary structure Ab epitopes linked to protection and developed reagents (human monoclonal Abs, recombinant DENVs) and assays that precisely measure Ab epitope-specific responses in human sera. In collaboration with Sanofi Pasture, we will use samples from the CYD-TDV efficacy trials, including several hundred samples from people who experienced vaccine breakthrough infections, to identify Ab epitope based correlates of protective immunity. Currently we are the only group capable of doing this study because no other dengue vaccine has been tested in efficacy studies. As DENV vaccines have 4 attenuated replicating viruses, it has been difficult to obtain balanced replication and immunity to all 4 serotypes. Currently there are no reliable models to optimize the formulation of multi-component live dengue vaccine formulations. Investigators at Sanofi Pasteur's VaxDesign campus have developed a fully automated human Peripheral Tissue Equivalent (PTE) biomimetic model for preclinical evaluation of vaccines. As DENVs initially replicate in peripheral tissues after mosquito transmission or vaccination, we will test if the PTE biomimetic model has utility for predicting and optimizing the replication of single and multicomponent live-attenuated dengue vaccines. Within the time frame of this study, we will establish novel standardized assays for supporting global efforts to develop dengue vaccines.

计划概要 登革热是人类最常见的节肢动物传播的病毒性疾病。迫切需要疫苗 预防登革热，但疫苗开发因四种登革热病毒 (DENV) 的存在而变得复杂 血清型和免疫增强登革热疾病的可能性。主要候选疫苗包含 4 减毒活病毒涵盖 4 种血清型。最先进的候选疫苗，嵌合黄 赛诺菲巴斯德开发的发烧登革热四价活病毒疫苗（CYD-TDV）最近经过评估 在亚洲和拉丁美洲进行的人体功效研究中。总体而言，CYD-TDV 可有效减少 接种疫苗的人群中登革热疾病的负担。然而，疫苗的含量出乎意料地低 与暴露于登革热的受试者相比，对登革热病毒血清型 2 (DENV2) 和未接触过登革热的受试者的功效 接种疫苗的受试者。这些群体的功效较低是出乎意料的，因为疫苗 在这些受试者中诱导中和抗体（Abs）。该提案的中心假设是 细胞培养中和抗体的质量（抗体表位特异性）而不是总量是更好的预测因子 DENV 疫苗在人群中的表现。此外，由于 DENV 复合体有 4 种血清型， 疫苗将用于混合了幼稚个体和部分免疫个体的人群，免疫检测 基于单一表位的方法不太可能预测针对 4 种血清型的功效。 该项目以我们实验室的研究为基础，旨在了解保护性和致病性抗体 暴露于自然登革热病毒感染的人的反应。我们发现了新的四级结构Ab 与保护相关的表位和开发的试剂（人单克隆抗体、重组 DENV）以及 精确测量人类血清中抗体表位特异性反应的检测方法。与赛诺菲合作 牧场，我们将使用 CYD-TDV 功效试验的样本，包括来自 经历过疫苗突破性感染的人，以确定基于抗体表位的保护性相关性 免疫。目前我们是唯一有能力进行这项研究的小组，因为没有其他登革热疫苗可以 已在功效研究中进行了测试。 由于DENV疫苗有4种减毒复制病毒，因此很难获得平衡的疫苗 对所有 4 种血清型的复制和免疫。目前尚无可靠的模型来优化配方 多组分活登革热疫苗制剂。赛诺菲巴斯德 VaxDesign 园区的研究人员 开发了一种用于临床前研究的全自动人体外周组织等效物（PTE）仿生模型 疫苗评估。由于 DENV 在蚊子传播或传播后最初在外周组织中复制， 疫苗接种后，我们将测试 PTE 仿生模型是否可用于预测和优化疫苗的复制 单组分和多组分登革热减毒活疫苗。 在本研究的时间范围内，我们将建立新的标准化检测方法来支持全球 努力开发登革热疫苗。

项目成果

Antigenic Variation of the Dengue Virus 2 Genotypes Impacts the Neutralization Activity of Human Antibodies in Vaccinees.

• DOI: 10.1016/j.celrep.2020.108226
• 发表时间: 2020-10-06
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Martinez DR;Yount B;Nivarthi U;Munt JE;Delacruz MJ;Whitehead SS;Durbin AP;de Silva AM;Baric RS
• 通讯作者: Baric RS

Determining dengue virus serostatus by indirect IgG ELISA compared with focus reduction neutralisation test in children in Cebu, Philippines: a prospective population-based study.

• DOI: 10.1016/s2214-109x(20)30392-2
• 发表时间: 2021-01
• 期刊: LANCET GLOBAL HEALTH
• 影响因子: 34.3
• 作者: Lena Lopez, Anna;Adams, Cameron;Ylade, Michelle;Jadi, Ramesh;Veronica Daag, Jedas;Molloy, Caitlyn T.;An Agrupis, Kristal;Kim, Deok Ryun;Silva, Maria Wilda;Yoon, In-Kyu;White, Laura;Deen, Jacqueline;de Silva, Aravinda M.
• 通讯作者: de Silva, Aravinda M.

Vaccine-induced antibodies to contemporary strains of dengue virus type 4 show a mechanistic correlate of protective immunity.

• DOI: 10.1016/j.celrep.2022.110930
• 发表时间: 2022-06-07
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Gallichotte, Emily N.;Henein, Sandra;Nivarthi, Usha;Delacruz, Matthew;Scobey, Trevor;Bonaparte, Matthew;Moser, Janice;Munteanu, Alina;Baric, Ralph;de Silva, Aravinda M.
• 通讯作者: de Silva, Aravinda M.

Generation of Mature DENVs via Genetic Modification and Directed Evolution.

• DOI: 10.1128/mbio.00386-22
• 发表时间: 2022-06-28
• 期刊: mBio
• 影响因子: 6.4