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

基本信息

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
项目类别：
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

项目摘要

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-寨卡疫苗，提供针对登革热 (DENV1-4) 和寨卡 (ZIKV) 病毒的四种血清型具有最大的安全性和有效性。到迄今为止，黄病毒疫苗的开发重点是诱导中和抗体（nAb），如它们被认为是防止自然感染的关键机制。然而， DENV 和 ZIKV 的不同寻常之处在于，抗体对疫苗接种或先前感染的反应较弱，在随后的感染和发病机制中诱导抗体依赖性增强（ADE）再次感染。事实上，鉴于儿童中存在严重后遗症的 DENV 疾病，目前唯一获得许可的 DENV 疫苗。因此，该应用程序的主要目标是开发一个针对 DENV 和 ZIKV 的有效疫苗，但不能介导 ADE。我们假设这种疫苗需要引发强烈的 nAb 反应和强烈的 T 细胞效应反应，以抵消任何 ADE 介导 Ab 的存在，基于我们调查 Ab 和 T 细胞对 DENV 和 ZIKV 的反应。特别是，我们已经证明 CD8 T 细胞介导交叉防止异型 DENV 和 ZIKV 感染，并且 DENV 疫苗诱导 CD8 T 细胞可以预防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 仅引发 T 细胞而非 nAb 反应，并提供针对 ZIKV 的保护对小鼠的挑战。因此，我们假设我们的 DENV-ZIKV 组合疫苗表达两种 Ab- DENV1-4和ZIKV的T细胞靶向蛋白将产生体液和细胞免疫反应提供针对所有五种病毒的强大、长期的保护。我们将通过实现来检验这个假设具体目标如下： 1) 评估 DENV-ZIKV 疫苗的免疫原性和功效。 2) 至确定 DENV-ZIKV 疫苗诱导的保护作用的持久性和机制基础免疫。