Novel Chikungunya vaccine with rearranged genome

基因组重新排列的新型基孔肯雅疫苗

• 批准号: 10010405
• 负责人: Peter M. Pushko
• 金额: $ 12.08万
• 依托单位: MEDIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-03 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010405
• 关键词: Achievement; Address; Adjuvant; Advanced Development; Adverse reactions; Aedes; Africa; Alphavirus; Americas; Animal Model; Arthralgia; Arthritis; Asia; Attenuated; Attenuated Live Virus Vaccine; Bacteria; CMV promoter; Capsid; Cells; Characteristics; Chikungunya fever; Chikungunya virus; Clinical; Clinical Trials; Cold Chains; Consultations; Containment; Culicidae; DNA; DNA Sequence Rearrangement; DNA Vaccines; Development; Disease Outbreaks; Dose; Ecological Change; Electroporation; Epidemic; Epitopes; Evaluation; Fever; Formulation; Genes; Genetic; Genome; Glycoproteins; Growth; Heterogeneity; Human; Immunity; Immunization; Immunocompetent; In Vitro; Inbred BALB C Mice; Inbreeding; Individual; Infection; Infection Control; Injections; International; Intramuscular; Investigation; Legal patent; Length; Liposomes; Mediating; Mus; Mutation; National Institute of Allergy and Infectious Disease; Natural Immunity; Patients; Phase; Phase II Clinical Trials; Phenotype; Plasmids; Population Density; Populations at Risk; Probability; Production; Proteins; RNA; Recording of previous events; Resistance; Risk; Safety; Small Business Innovation Research Grant; Technology; Testing; Transfection; Travel; Vaccination; Vaccine Design; Vaccines; Vero Cells; Viral; Viral Genome; Viral Vaccines; Viremia; Virus; Virus Diseases; Work; attenuation; base; chikungunya; climate change; early phase clinical trial; genetic vaccine; genomic RNA; immunogenic; immunogenicity; improved; mosquito-borne; mouse model; neutralizing antibody; next generation sequencing; nonhuman primate; novel; novel vaccines; pandemic disease; plasmid DNA; prevent; protective efficacy; prototype; response; urban area; vaccine candidate; vaccine development; vector

ABSTRACT Chikungunya fever virus (CHIKV) is a mosquito-borne alphavirus that causes wide-spread human infections and epidemics in Asia, Africa and recently, in the Americas. There is an increased risk of CHIKV pandemic due to climate and ecological change and international travel. Currently, there is no approved vaccine. Previous experimental approaches include the US Army-developed IND vaccine, 181/25, that contains two attenuating mutations in the E2 protein. The 181/25 vaccine showed high immunogenicity in Phase II clinical trial; however, adverse reactions justify the need for safety improvement. Medigen has developed a DNA-launched, live-attenuated vaccine, termed iDNA®, in which the full-length genome of the 181/25 IND vaccine virus is transcribed from a CMV promoter on a plasmid. Injection of the plasmid intramuscularly launches the live-attenuated vaccine virus. This approach has the advantages of DNA vaccines, including the encoding of the vaccine virus by a genetically stable DNA plasmid, and the high efficacy of live-attenuated vaccines. To address the need for improved safety of the 181/25 vaccine, we propose a genomic rearrangement as an additional attenuating mutation. This genomic rearrangement (RA181/25) does not change immunogenic epitopes but is resistant to reversion since multiple, independent mutations would be needed for reversion. In Specific Aim 1, we prepare the rearranged (RA181/25) CHIKV iDNA vaccine and evaluate it in vitro for plaque phenotype, growth curve, and genetic stability by next generation sequencing (NGS), as compared to non- rearranged iDNA and the 181/25 IND vaccine virus. In Specific Aim 2, RA181/25 CHIKV iDNA is evaluated in two mouse models (inbred C57BL/6 and outbred CD-1) as compared to the non-rearranged CHIKV iDNA and the 181/25 IND vaccine virus. We propose to use electroporation, microneedles, and liposomal formulations to optimize the iDNA vaccination, and we will evaluate safety, immunogenicity (neutralizing antibody and cell-mediated responses), and protective efficacy against CHIKV challenge in both animal models. The successful proof-of-concept demonstration of a safety advantage of the RA181/25 CHIKV iDNA vaccine would advance a novel single-dose vaccine with many advantages for protecting populations at risk for CHIKV infection, as well as for rapidly controlling CHIKV outbreaks.

摘要 基孔肯雅热病毒(CHIKV)是一种蚊媒甲型病毒，可引起广泛传播的人类 在亚洲、非洲以及最近在美洲的感染和流行。患CHIKV的风险增加 气候和生态变化以及国际旅行造成的大流行。目前，没有审批通过的 疫苗。之前的实验方法包括美国军队开发的IND疫苗，181/25，即 在E2蛋白中包含两个衰减性突变。181/25疫苗表现出较高的免疫原性 第二阶段临床试验；然而，不良反应证明有必要改进安全性。梅迪根有 开发了一种DNA发射的活体减毒疫苗，名为IDNA®，在该疫苗中， 181/25IND疫苗病毒是由CMV启动子转录而来的。注射质粒 肌肉注射产生减毒活疫苗病毒。这种方法具有DNA的优点 疫苗，包括用遗传稳定的DNA质粒编码疫苗病毒，以及高效 减毒活疫苗。 为了解决181/25疫苗安全性提高的需要，我们建议将基因组重排作为 一个额外的衰减性突变。这种基因组重排(RA181/25)不会改变免疫原性 但对逆转有抵抗力，因为逆转需要多个独立的突变。在……里面 具体目的1，我们制备了重排(RA181/25)CHIKV Idna疫苗，并对其进行了体外斑块检测 下一代测序(NGS)的表型、生长曲线和遗传稳定性 重排的IDNA和181/25 IND疫苗病毒。在具体目标2中，对RA181/25 CHIKV IDNA进行了评估 两种小鼠模型(近交系C57BL/6和近交系CD-1)与未重组CHIKV Idna的比较 以及181/25年的IND疫苗病毒。我们建议使用电穿孔、微针和脂质体。 配方以优化IDNA疫苗接种，我们将评估安全性、免疫原性(中和 抗体和细胞介导的反应)，以及对CHIKV攻击的保护效果 模特们。RA181/25 CHIKV IDNA的概念验证成功证明了其安全优势 疫苗将推动一种新的单剂疫苗的发展，该疫苗具有保护高危人群的许多优点 用于CHIKV感染以及快速控制CHIKV疫情。