Dengue virus mRNA lipid nanoparticle vaccine

登革热病毒mRNA脂质纳米颗粒疫苗

• 批准号: 10297308
• 负责人: Justin Richner
• 金额: $ 45.41万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-12 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297308
• 关键词: Adoptive Transfer; Animal Model; Animals; Antibodies; Antibody Repertoire; Antibody-Dependent Enhancement; Antigens; Antiviral Agents; B-Lymphocytes; Bite; Blood Pressure; Cells; Cessation of life; Clinical; Clinical Trials; Contracts; Culicidae; Data; Dengue; Dengue Vaccine; Dengue Virus; Dengvaxia; Disease; Engineering; Epitopes; Evaluation; Extravasation; Fever; Flavivirus; Future; Glycoproteins; Health; Hemorrhage; Human; Immune; Immune response; Immunity; Immunocompetent; Individual; Infection; Lead; Maps; Measures; Membrane; Messenger RNA; Monitor; Mus; Mutate; Nucleosides; Organ failure; Plasma; Population; Predisposition; Pregnant Women; Primary Infection; Probability; Protein Biosynthesis; RNA vaccine; Refractory; Risk; Serotyping; Serum; Severity of illness; Shock; Structure; Surface; Symptoms; T-Lymphocyte; T-Lymphocyte Epitopes; Techniques; Therapeutic; Vaccinated; Vaccination; Vaccines; Viral; Viral Proteins; Virion; Virus Diseases; Zika Virus; cell mediated immune response; combat; cross reactivity; design; env Gene Products; experimental study; hospitalization rates; immunogenicity; immunosuppressed; in vivo; lipid nanoparticle; mRNA delivery; mouse model; neutralizing antibody; nonhuman primate; novel; novel vaccines; particle; pathogen; polyclonal antibody; pre-clinical; protective efficacy; response; secondary infection; severe dengue; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine safety

Nearly 400 million people are infected with dengue virus (DENV) each year through the bite of infected mosquitos concentrated in the tropical and subtropical regions of the world. Symptoms can range from febrile illness to severe dengue that manifests as plasma leakage, sudden loss of blood pressure, organ failure, and shock that can ultimately lead to death. Severe dengue complications are often associated with a secondary heterotypic infection of one of the four circulating serotypes. In this scenario, humoral immune responses targeting cross- reactive, poorly-neutralizing epitopes lead to increased infectivity of susceptible cells via antibody-dependent enhancement (ADE). Additionally, DENV immunity has been implicated in increased susceptibility to Zika virus through ADE. Currently there are no available therapeutics to combat DENV disease. Dengvaxia, the only licensed DENV vaccine, was found to increase hospitalization rates in naïve populations, and thus is not recommended for a large portion of at-risk individuals. There is an urgent need for a safe and efficacious vaccine that elicits a robust, balanced, neutralizing response to all four DENV serotypes. We propose to develop a novel DENV vaccine utilizing an emergent platform: mRNA encoding for viral proteins encapsidated in a lipid nanoparticle (LNP). mRNA-LNP vaccines elicit robust humoral and cell-mediated immune responses in a safe, non-infectious platform. Additionally, we can direct the host immune response towards neutralizing epitopes by mutating the mRNA encoding for the viral protein. We hypothesize that a sequence-engineered tetravalent mRNA-LNP vaccine will induce a balanced, protective immune response against all four serotypes of dengue without the potential of causing immune enhancement and ADE. In Aim 1 of this study we will generate and optimize mRNA constructs encoding for the pre-membrane and envelope viral glycoproteins for all four serotypes of DENV. We will mutate the poorly-neutralizing, cross-reactive epitopes that drive ADE. In Aim 2 we will characterize the immune response to the vaccines in a mouse model. In addition to quantifying humoral and cellular immune responses, we will also measure the immune enhancement capacity of all vaccines. In Aim 3, we will evaluate vaccine efficacy and safety in susceptible mouse models, by challenging vaccinated mice with different DENV serotypes to monitor protection and ADE. We will also determine mechanism of protection via adoptive transfer experiments. Through this study, we will identify DENV vaccines that demonstrate broad protection and lack of immune enhancement for further evaluation as candidate human vaccines.

每年有近4亿人通过感染的蚊子感染了粉丝（DENV） 集中在世界的热带和亚热带地区。症状的范围从高热疾病到 表现为血浆泄漏的严重风扇，血压突然损失，器官衰竭和震惊 最终可能导致死亡。严重的风扇通常与次级异型有关 感染四种循环血清型之一。在这种情况下，针对交叉的体液免疫反应 反应性，不中和的表位导致易感细胞通过抗体依赖的感染增加 增强（ADE）。此外，DENV免疫与对寨卡病毒的敏感性增加有关 通过Ade。目前尚无对抗DENV疾病的可用疗法。登伐氏症，唯一 发现有执照的DENV疫苗，发现幼稚的人口中的住院率，因此不是 推荐给大部分高危个人。迫切需要安全有效的疫苗 这引起了对所有四种DENV血清型的强大，平衡，中和的反应。我们建议开发小说 使用紧急平台的DENV疫苗：封装在脂质中的病毒蛋白的mRNA编码 纳米颗粒（LNP）。 mRNA-LNP疫苗在安全的， 非感染平台。此外，我们可以将宿主免疫反应引导到中和表位 突变编码病毒蛋白的mRNA。我们假设序列工程的四维体 mRNA-LNP疫苗将针对所有四种血清型诱导平衡，受保护的免疫反应 登革热没有引起免疫增强和ADE的潜力。在本研究的目标1中，我们将 生成并优化编码所有编码前膜和包膜病毒糖蛋白的mRNA构建体 DENV的四种血清型。我们将突变驱动ADE的不利性，交叉反应的表位。目标 2我们将在小鼠模型中表征对疫苗的免疫响应。除了量化体液 和细胞免疫调查员，我们还将测量所有疫苗的免疫增强能力。目标 3，我们将通过挑战接种的小鼠来评估易感小鼠模型的疫苗效率和安全性 具有不同的DENV血清型来监视保护和ADE。我们还将确定保护机制 通过自适应转移实验。通过这项研究，我们将确定表现出广泛的DENV疫苗 作为候选人疫苗，保护和缺乏免疫原质以进一步评估。