Novel Chikungunya vaccine with rearranged genome

基因组重新排列的新型基孔肯雅疫苗

基本信息

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
项目类别：
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

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

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项目摘要

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.

抽象的基孔肯雅热病毒（Chikv）是一种蚊子 - 纳米α，导致广泛的人类亚洲，非洲以及最近在美洲的感染和发作。 CHIKV的风险增加了由于气候和生态变化和国际旅行而引起的大流行。目前，没有批准疫苗。以前的实验方法包括美国陆军开发的IND疫苗181/25，在E2蛋白中包含两个衰减突变。 181/25疫苗的免疫原性很高 II期临床试验；但是，不利反应证明了安全改善的必要性。 Medigen拥有开发了一种DNA启动的，活衰减的疫苗，称为IDNA®，其中全长基因组的全长基因组 181/25 IND疫苗病毒在质粒上从CMV启动子转录。注射质粒室内发射活体内疫苗病毒。这种方法具有DNA的优势疫苗，包括通过遗传稳定的DNA质粒编码疫苗病毒的疫苗和高效率实时疫苗。为了满足提高181/25疫苗安全性的需求，我们提出了一个基因组重排作为额外的衰减突变。这种基因组重排（RA181/25）不会改变免疫原性表位，但抗反向，因为需要多个独立的突变才能进行反向。在特定目标1，我们准备重新排列的（RA181/25）Chikv IDNA疫苗并在体外评估斑块与非 - 重新排列的IDNA和181/25 IND疫苗病毒。在特定的目标2中，评估了RA181/25 CHIKV IDNA 与非重新编号的Chikv IDNA相比以及181/25 IND疫苗病毒。我们建议使用电穿孔，微针和脂质体公式优化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），并保护两种动物的CHIKV挑战的效率型号。 RA181/25 CHIKV IDNA的安全优势的成功概念证明疫苗将推进一种新型的单剂量疫苗，并具有许多优势来保护处于危险的人群对于CHIKV感染，以及快速控制Chikv爆发的情况。