Development of a Replicon RNA-based Vaccine against Dengue and Zika

开发基于复制子 RNA 的登革热和寨卡疫苗

• 批准号: 10413253
• 负责人: Sujan Shresta
• 金额: $ 71.27万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413253
• 关键词: Address; Adoptive Transfer; Adult; Alphavirus; Antibody Formation; Antibody Response; Antibody-Dependent Enhancement; Antigens; Avidity; Binding; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cellular Immunity; Child; Clinical Trials; Combined Vaccines; Data; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Development; Disease; Disease Outbreaks; Dose; Epidemic; Epitopes; Flavivirus; Frequencies; Goals; Guillain Barré Syndrome; Healthcare Systems; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunize; Infant; Infection; Measures; Mediating; Morbidity - disease rate; Mus; Nonstructural Protein; Pathogenesis; Persons; Phenotype; Population; Proteins; RNA; RNA vaccine; Replicon; Risk; Safety; Serotyping; Severity of illness; T cell response; T-Cell Depletion; T-Lymphocyte; Testing; Vaccinated; Vaccination; Vaccines; Viral Proteins; Virus; Wild Type Mouse; Work; ZIKA; ZIKV infection; Zika Virus; Zika virus vaccine; base; combinatorial; congenital zika syndrome; cross immunity; cross reactivity; design; effector T cell; immunogenicity; improved; mortality; neonate; neutralizing antibody; prevent; public health priorities; replicon vaccine; response; severe dengue; type I interferon receptor; vaccine development; vaccine response; vaccine strategy

ABSTRACT The long-term goal of this project is to develop a dengue-Zika vaccine that provides protection against the four serotypes of dengue (DENV1-4) and Zika (ZIKV) viruses with maximal safety and efficacy. To date, flavivirus vaccine development has focused on the induction of neutralizing antibodies (nAbs), as they have been assumed to be the key mechanism for protection against natural infection. However, DENV and perhaps ZIKV are unusual in that weak Ab responses to vaccination or prior infection can induce antibody-dependent enhancement (ADE) of infection and pathogenesis during subsequent reinfections. In fact, DENV disease with severe sequalae has been documented in children given the only currently licensed DENV vaccine. Thus, the primary objective of this application is to develop an effective vaccine against DENV and ZIKV that cannot mediate ADE. We hypothesize that this vaccine will need to elicit both strong nAb responses and strong T cell effector responses that will counterbalance the presence of any ADE-mediating Abs, based on our work investigating the interplay between Ab and T cell responses to DENV and ZIKV. In particular, we have shown that CD8 T cells mediate cross- protection against heterotypic DENV and ZIKV infections, and that DENV vaccine-elicited CD8 T cells can prevent ADE. In addition, our preliminary data show that an RNA replicon-based vaccine expressing ZIKV nonstructural protein 3 elicits only T cell but not nAb responses and confers protection against ZIKV challenge in mice. Thus, we hypothesize that our combinatorial DENV-ZIKV vaccine expressing both Ab- and T cell-targeting proteins of DENV1-4 and ZIKV will produce humoral and cellular immune responses that provide robust, long-term protection against all five viruses. We will test this hypothesis by achieving the following Specific Aims: 1) To evaluate immunogenicity and efficacy of a DENV-ZIKV vaccine. 2) To determine the durability and mechanistic underpinnings of DENV-ZIKV vaccine-induced protective immunity.

抽象的 该项目的长期目标是开发一种登革热Zika疫苗，可保护 具有最大安全性和功效的登革热（DENV1-4）和Zika（Zikv）病毒的四种血清型。到 日期，黄素病毒疫苗的开发集中于中和抗体（NABS）的诱导 他们被认为是防止自然感染的关键机制。然而， DENV，也许ZIKV是不寻常的，因为AB对疫苗接种或事先感染的反应可以 随后的感染和发病机理诱导抗体依赖性增强（ADE） 恢复。实际上，鉴于儿童已经记录 目前仅获得许可的DENV疫苗。因此，此应用程序的主要目的是开发 无法介导ADE的DENV和ZIKV的有效疫苗。我们假设这种疫苗 将需要引起强大的NAB响应和强大的T细胞效应子响应，这将平衡 根据我们研究AB和AB之间的相互作用的工作 T细胞对DENV和ZIKV的反应。特别是，我们表明CD8 T细胞介导了交叉 防止异型DENV和ZIKV感染，并保护DENV疫苗的CD8 T细胞 可以防止ADE。此外，我们的初步数据表明，基于RNA复制子的疫苗表达 ZIKV非结构蛋白3仅引起T细胞，但不引起NAB响应并赋予对ZIKV的保护 小鼠的挑战。因此，我们假设我们的组合DENV-ZIKV疫苗都表达了两者 DENV1-4和ZIKV的T细胞靶向蛋白将产生体液和细胞免疫反应 这为所有五种病毒提供了强大的长期保护。我们将通过实现来检验这一假设 以下具体目的：1）评估DENV-ZIKV疫苗的免疫原性和功效。 2）到 确定DENV-ZIKV疫苗诱导的保护性的耐用性和机械基础 免疫。