Dengue virus mRNA lipid nanoparticle vaccine

登革热病毒mRNA脂质纳米颗粒疫苗

• 批准号: 10655483
• 负责人: Justin Richner
• 金额: $ 61.41万
• 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/10655483
• 关键词: Adoptive Transfer; Animal Model; Animals; Antibodies; Antibody Repertoire; Antibody-Dependent Enhancement; Antigens; 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; Licensing; Maps; Measures; Membrane; Membrane Proteins; Messenger RNA; Modeling; Monitor; Mus; Mutate; Nucleosides; Organ failure; Persons; 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; Technology; Therapeutic; Vaccinated; Vaccination; Vaccinee; 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; nonhuman primate; novel; novel vaccines; particle; pathogen; polyclonal antibody; pre-clinical; protective efficacy; response; secondary infection; severe dengue; transmission process; vaccine candidate; vaccine efficacy; vaccine evaluation; vaccine formulation; vaccine immunogenicity; 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 亿人通过受感染的蚊子叮咬感染登革热病毒 (DENV) 集中出现在世界热带和亚热带地区。症状包括发热性疾病等。 严重登革热，表现为血浆渗漏、血压突然下降、器官衰竭和休克， 最终可导致死亡的严重登革热并发症通常与继发性异型相关。 在这种情况下，四种循环血清型之一的感染，针对交叉的体液免疫反应。 反应性、中和性差的表位通过抗体依赖性导致易感细胞的感染性增加 此外，DENV 免疫力与寨卡病毒易感性增加有关。 目前没有可用的治疗方法来对抗 Dengvaxia。 经许可的 DENV 疫苗被发现会增加未接种人群的住院率，因此不 建议大部分高危人群使用 迫切需要一种安全有效的疫苗。 从而对所有四种 DENV 血清型产生强有力的、平衡的、中和的反应。我们建议开发一种新型的。 DENV 疫苗利用新兴平台：编码封装在脂质中的病毒蛋白的 mRNA 纳米颗粒 (LNP) mRNA-LNP 疫苗可在安全、安全的情况下引发强大的体液和细胞介导的免疫反应。 此外，我们可以通过中和表位来引导宿主免疫反应。 我们勇敢地突变了编码病毒蛋白的 mRNA。 mRNA-LNP 疫苗将诱导针对所有四种血清型的平衡的保护性免疫反应 登革热不会引起免疫增强和 ADE 在本研究的目标 1 中，我们将。 生成并优化编码所有包膜前膜和病毒糖蛋白的 mRNA 构建体 我们将对驱动 ADE 的中和性差、交叉反应性表位进行突变。 2 除了量化体液外，我们还将在小鼠模型中表征对疫苗的免疫反应。 和细胞免疫反应，我们还将测量所有疫苗的免疫增强能力。 3、我们将通过挑战疫苗小鼠来评估疫苗在易感小鼠模型中的功效和安全性 用不同的 DENV 血清型来监测保护和 ADE 我们还将确定保护机制。 通过过继转移实验，我们将确定具有广泛应用前景的 DENV 疫苗。 保护和缺乏免疫增强作用，以作为候选人类疫苗进行进一步评估。

项目成果

mRNA induced expression of human angiotensin-converting enzyme 2 in mice for the study of the adaptive immune response to severe acute respiratory syndrome coronavirus 2.

• DOI: 10.1371/journal.ppat.1009163
• 发表时间: 2020-12
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Hassert M;Geerling E;Stone ET;Steffen TL;Feldman MS;Dickson AL;Class J;Richner JM;Brien JD;Pinto AK
• 通讯作者: Pinto AK

Type I IFN stimulates lymph node stromal cells from adult and old mice during a West Nile virus infection.

• DOI: 10.1111/acel.13796
• 发表时间: 2023-04
• 期刊: Aging cell
• 影响因子: 7.8