A novel DNA-launched live attenuated Chikungunya vaccine

一种新型 DNA 发射的基孔肯雅热减毒活疫苗

• 批准号: 8191054
• 负责人: Peter M. Pushko
• 金额: $ 8.72万
• 依托单位: MEDIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191054
• 关键词: Adjuvant; Aedes; Africa; Age; Alphavirus; Area; Asia; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Bioterrorism; Cell Culture Techniques; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Chikungunya virus; Clinical; Codon Nucleotides; Cold Chains; Collaborations; Combined Vaccines; Complementary DNA; Containment; DNA; DNA Vaccines; DNA delivery; Development; Disease Outbreaks; Dose; Electroporation; Emergency Situation; Epidemic; Europe; Evaluation; Family; Fever; Functional RNA; Genes; Genetic; Genetic Heterogeneity; Genetic Transcription; Genome; Genomics; Goals; Hamsters; Human; Hybrids; Immune; Immune Sera; Immune response; Immunity; Immunization; In Vitro; India; Individual; Infection; Injection of therapeutic agent; Intramuscular Injections; Lead; Length; Licensing; Life; Molecular Cloning; Mosquito-borne infectious disease; Mus; Mutagenesis; Mutation; Phenotype; Plasmids; Polyethyleneimine; Population; Pre-Clinical Model; Production; Public Health; RNA; Recombinants; Research; Safety; Signal Transduction; Silent Mutation; Solutions; Technology; Testing; Tissues; Togaviridae; Transfection; Universities; Vaccination; Vaccine Antigen; Vaccines; Variant; Virulent; Virus; Virus Diseases; Work; aged; chikungunya; cost; design; immunogenicity; immunosuppressed; improved; in vivo; innovation; manufacturing scale-up; member; neutralizing antibody; new technology; novel; novel vaccines; pathogen; plasmid DNA; prevent; promoter; vaccine delivery; vaccine safety; vector mosquito; viral RNA

DESCRIPTION (provided by applicant): The main goal of this application is the design, production and evaluation of a conceptually novel vaccine against Chikungunya virus (CHIKV). We propose a novel technology of "infectious" DNA (i-DNA) as CHIKV vaccine. A unique feature of this technology is that live attenuated CHIKV vaccine is launched in vivo from the i-DNA plasmid. In the i-DNA, the full-length copy of RNA genome of modified live attenuated IND vaccine 181/25 is placed in the plasmid in the context of optimized eukaryotic promoter and regulatory sequences. Transcription of the genomic viral RNA in vivo results in limited replication of attenuated virus in the tissues of vaccine recipient and induction of a protective immune response. Since the i-DNA represents a molecular clone, it will generate a uniform population of attenuated virus thus potentially improving safety. We will also prepare two i-DNA variants by de-optimization of translational codons within C-E2-E1 genes with the view to enhance genetic stability and vaccine safety. Experimental CHIKV i-DNA vaccines will be evaluated in vitro and in vivo along with the current 181/25 live attenuated vaccine. The vaccine antigens will be probed with a panel of human antisera from recent clinical CHIKV isolates in partnership with Sri Ramachandra University, Chennai, India. Immunogenicity and safety profiles will be determined in the young and aged mice as well as in immunosuppressed hamsters. Thus, characteristics of candidate i-DNA vaccines will be evaluated in the preclinical models of various age and immune status, which mimics human population and will provide accurate determination of safety and immunogenicity profiles of the vaccines. In summary, i-DNA vaccination will combine the simplicity of DNA vaccines with the exceptional efficacy of live attenuated vaccines. The i-DNA can potentially improve safety, does not require cold chain and is easy to manufacture and scale-up in emergency scenarios. Further, bacterially generated i-DNA will contain CpG motifs, which are expected to activate innate immune responses and improve immunogenicity. If successful, this technology may represent a revolutionary solution for vaccination against Chikungunya fever. PUBLIC HEALTH RELEVANCE: Chikungunya virus (CHIKV) is an emerging pathogen and a public health concern worldwide. The focus of this study is the design, production and evaluation of a conceptually novel vaccine against CHIKV. We hypothesize that safety and immunogenicity of live attenuated CHIKV vaccine can be improved by using the "infectious" DNA technology (i-DNA). This will result in a unique CHIKV vaccine, which will combine the simplicity of DNA vaccines with the exceptional efficacy of live attenuated vaccine. Such vaccine can be rapidly deployed during outbreaks and prevent spread of infection to non-affected areas.

描述(由申请人提供)：本申请的主要目标是设计、生产和评估一种概念性的基孔肯雅病毒(CHIKV)疫苗。我们提出了一种“感染性”DNA(I-DNA)作为CHIKV疫苗的新技术。这项技术的一个独特之处在于，CHIKV减毒活疫苗是从I-DNA质粒体内发射的。在I-DNA中，将修饰的IND减毒活疫苗181/25的RNA基因组全长拷贝置于优化的真核启动子和调控序列的背景下。病毒基因组RNA在体内的转录导致减毒病毒在疫苗接受者组织中的有限复制和保护性免疫反应的诱导。由于i-DNA代表一个分子克隆，它将产生一个统一的减毒病毒种群，从而潜在地提高安全性。我们还将通过去优化C-E2-E1基因中的翻译密码子来制备两个I-DNA变体，以期提高遗传稳定性和疫苗安全性。正在试验的CHIKV I-DNA疫苗将与目前的181/25减毒活疫苗一起在体外和体内进行评估。疫苗抗原将与印度金奈的SRI Ramachandra大学合作，用来自最近临床CHIKV分离株的一组人抗血清进行探测。将在幼鼠和老年鼠以及免疫抑制的仓鼠中确定免疫原性和安全性。因此，候选I-DNA疫苗的特性将在不同年龄和免疫状态的临床前模型中进行评估，这将模拟人类群体，并将准确地确定疫苗的安全性和免疫原性。总而言之，i-DNA疫苗将结合DNA疫苗的简单性和减毒活疫苗的非凡效力。I-DNA可以潜在地提高安全性，不需要冷链，并且在紧急情况下易于制造和扩大规模。此外，细菌产生的I-DNA将包含CpG基序，有望激活先天免疫反应，提高免疫原性。如果成功，这项技术可能代表着基孔肯雅热疫苗接种的革命性解决方案。 公共卫生意义：基孔肯雅病毒(CHIKV)是一种新出现的病原体，是全球公共卫生问题。这项研究的重点是设计、生产和评价一种概念性的新型CHIKV疫苗。我们推测，利用“感染性”DNA技术(i-DNA)可以提高CHIKV减毒活疫苗的安全性和免疫原性。这将产生一种独特的CHIKV疫苗，它将结合DNA疫苗的简单性和减毒活疫苗的非凡效力。这种疫苗可以在暴发期间迅速部署，并防止感染传播到未受影响的地区。