Assessment of the Immunogenicity and Protective Efficacy of a Multiagent DNA Vacc

多剂 DNA 疫苗的免疫原性和保护功效评估

• 批准号: 7938762
• 负责人: Connie Schmaljohn
• 金额: $ 103.13万
• 依托单位: GENEVA FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938762
• 关键词: Address; Adenovirus Vector; Adenoviruses; Advanced Development; Alphavirus; Antibodies; Categories; Cell Culture Techniques; Clinical Research; Clinical Trials; Codon Nucleotides; Combined Vaccines; DNA; DNA Vaccines; Democratic Republic of the Congo; Development; Devices; Disease; Dose; Drug Formulations; Ebola virus; Electroporation; Encephalitis Viruses; Equine Encephalomyelitis; Family member; Filoviridae; Filovirus; Funding; Gene Delivery; Genes; Glycoproteins; Goals; Human; Human Development; Immune response; Immunity; Immunization; Individual; Infection; Intramuscular; Licensing; Life; Measures; Membrane Glycoproteins; Methods; Monkeys; Mus; Muscle; National Institute of Allergy and Infectious Disease; Performance; Phase; Principal Investigator; Proteins; Recombinants; Regimen; Research; Rodent; Route; Safety; Skin; Sudan; System; Technology; Testing; Vaccinated; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral Hemorrhagic Fevers; Virus; biodefense; cell mediated immune response; dosage; flexibility; gene gun; immunogenicity; improved; in vivo; mortality; nonhuman primate; pathogen; prevent; protective efficacy; response; success; vaccine candidate; vaccine delivery; vaccine development; vector

DESCRIPTION (provided by applicant): Ebola (EBOV) and Marburg (MARV) viruses are NIAID Category A pathogens and cause severe hemorrhagic fevers in humans and nonhuman primates with mortalities as high as 90%. There are currently no licensed vaccines for preventing disease caused by these viruses. Recent successes in eliciting protective immunity in nonhuman primates with recombinant vesicular stomatitis virus (VSV) or adenovirus- vectored EBOV or MARV vaccines suggest that effective vaccines can be developed. Despite the promising results, concerns have been raised about the use of these vaccine platforms in humans. The recombinant adenovirus vaccines are replication deficient; thus, very high doses are needed to induce protective immunity. More importantly, because adenoviruses are common human pathogens, most humans have pre- existing immunity, which greatly interferes with the ability of the vector to induce an immune response to the recombinant gene product. In addition to naturally occurring preexisting immunity, the broad use of recombinant adenovirus vectors complicates the field of vaccine development because vector antibodies induced as the result of vaccination would suppress the responses to an independent vaccine utilizing a similar delivery strategy. In contrast, the VSV vector is a live virus vaccine that does not commonly infect humans; however, it is a human pathogen and significant safety concerns about its use have been raised. By comparison, DNA vaccines have been proven safe in many human clinical trials and there is no possibility of vector immunity. While DNA vaccines have lacked sufficient potency in humans, the development of in vivo electroporation delivery systems has the potential to address this shortcoming. The requested funding will not only facilitate progress toward safe and effective combination vaccines for Ebola (EBOV) and Marburg (MARV) viruses, but will also advance the development of a vaccine delivery platform that has the capacity to address many of the performance attributes desired in the field of biodefense, namely a readily manufactured, stable vaccine with sufficient potency to provide protective efficacy against multiple pathogens after few immunizations. As such, the research proposed directly addresses the goals of this solicitation. Specific aims of the research are to: (1) Generate improved DNA vaccine constructs for two species of EBOV and two strains of MARV through codon-optimization of the GP genes of each virus; (2) Compare the immunogenicity of the individual DNA vaccine candidates when delivered to mice in various dosages using electroporation via intramuscular or intradermal routes; (3) Evaluate and compare the protective efficacy of combined vs. individual DNA vaccines in mice after immunization by electroporation; (4) Demonstrate the immunogenicity and protective efficacy of combined EBOV and MARV DNA vaccines in non-human primates.

描述（由申请人提供）：埃博拉病毒 (EBOV) 和马尔堡病毒 (MARV) 属于 NIAID A 类病原体，可引起人类和非人灵长类动物严重出血热，死亡率高达 90%。目前还没有获得许可的疫苗可以预防这些病毒引起的疾病。最近使用重组水泡性口炎病毒（VSV）或腺病毒载体的 EBOV 或 MARV 疫苗在非人灵长类动物中引发保护性免疫的成功表明可以开发出有效的疫苗。尽管取得了有希望的结果，但人们对这些疫苗平台在人类中的使用表示担忧。重组腺病毒疫苗复制缺陷；因此，需要非常高的剂量来诱导保护性免疫。更重要的是，由于腺病毒是人类常见的病原体，大多数人已有免疫力，这极大地干扰了载体诱导重组基因产物免疫反应的能力。除了天然存在的预先存在的免疫之外，重组腺病毒载体的广泛使用使疫苗开发领域变得复杂，因为由于疫苗接种而诱导的载体抗体会抑制对利用类似递送策略的独立疫苗的反应。相比之下，VSV 载体是一种活病毒疫苗，通常不会感染人类；然而，它是一种人类病原体，人们对其使用提出了重大的安全担忧。相比之下，DNA疫苗在许多人体临床试验中已被证明是安全的，不存在载体免疫的可能性。虽然 DNA 疫苗在人体中缺乏足够的效力，但体内电穿孔递送系统的开发有可能解决这一缺点。所申请的资金不仅将促进针对埃博拉病毒（EBOV）和马尔堡病毒（MARV）的安全有效的联合疫苗的研发，还将推动疫苗递送平台的开发，该平台能够满足生物防御领域所需的许多性能属性，即一种易于制造、稳定的疫苗，其效力足以在几次免疫后提供针对多种病原体的保护功效。因此，拟议的研究直接解决了本次征集的目标。研究的具体目标是：（1）通过对每种病毒的 GP 基因进行密码子优化，为两种 EBOV 和两种 MARV 株生成改进的 DNA 疫苗构建体； (2) 比较各个 DNA 候选疫苗在通过肌内或皮内途径使用电穿孔以不同剂量递送至小鼠时的免疫原性； (3) 评估并比较联合DNA疫苗与单独DNA疫苗对电穿孔免疫小鼠的保护效果； (4) 证明EBOV和MARV DNA联合疫苗在非人灵长类动物中的免疫原性和保护功效。