Pre-clinical evaluation of a Zika virus vaccine

寨卡病毒疫苗的临床前评估

• 批准号: 9294463
• 负责人: ANDREA GAMBOTTO
• 金额: $ 19.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-04 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294463
• 关键词: Adenoviruses; Adjuvant; Americas; Animals; Antigens; Antiviral Agents; Arthropods; Attention; Brazil; Clinical; Country; Culicidae; Cyclic AMP; Dengue; Development; Dimerization; Disease Outbreaks; Emergency Situation; Environment; Evaluation; Family; Flavivirus; Genes; Goals; Guillain-Barré Syndrome; Human; Humoral Immunities; Hygiene; IgG1; Immune response; Immunity; Immunization; Immunohistochemistry; Infection; Japanese Encephalitis; Literature; Measures; Microcephaly; Modeling; Monitor; Mus; Names; Newborn Infant; Nucleotides; Organ; Passive Immunity; Pathway interactions; Periodicity; Poly I-C; Recombinants; Regimen; Reporting; Subunit Vaccines; System; Testing; Titrations; Vaccinated; Vaccines; Virus; Virus Replication; Virus Shedding; West Nile virus; World Health Organization; Yellow Fever; Zika Virus; Zika virus vaccine; base; dimer; efficacy testing; extracellular; immunogenicity; in vivo; intraperitoneal; monomer; nervous system disorder; neutralizing antibody; pre-clinical; pregnant; receptor binding; recombinant virus; research clinical testing; response; socioeconomics; suckling; vaccine candidate; vaccine efficacy; vaccine trial; vector; vector-based vaccine; virus envelope

Abstract Since first detected in the Americas in May 2015 after rapidly spreading from Brazil, the mosquito-borne Zika virus (ZIKV) has attracted global attention. The ZIKV outbreak in Brazil has also been associated with a significant rise in the number of babies born with microcephaly and neurological disorders such as Guillain- Barré syndrome and has been declared a “global emergency” by the World Health Organization. Zika virus is related to dengue, yellow fever, Japanese encephalitis, and West Nile viruses, all of which are arthropod-borne flaviviruses. Building on successful flavivirus vaccine approaches reported in the literature as an initial attempt to develop a Zika virus vaccine, we have generated a panel of recombinant Zika virus subunit vaccines based on the extracellular portion of the ZIKV envelope gene or the EDIII domain of the ZIKV envelope gene. The EDIII loop of the flavivirus envelope gene is the receptor-binding domain and has been shown to be the most promising target for an antiviral neutralizing immunity. Both these antigens (E and EDIII) were generated as monomers (ZIKV-rE and ZIKV-rEDIII), as dimers in fusion with the fc portion of the human IgG1 (ZIKV-rEhIg and ZIKV-rEDIIIhIg), and as trimers in fusion with the T4 fibritin foldon trimerization domain (ZIKV-rEfl and ZIKV-rEDIIIfl). In the preliminary studies presented here, we tested the immunogenicity of trimeric ZIKV-rEfl and ZIKV-rEDIIIfl delivered transcutaneously using dissoluble microneedle array (MNA) delivery system into C57BL6 mice. The choice of the MNA-based antigen delivery system is justified because its efficacy and it is simple and easily adaptable to use in low hygiene and pure socio-economic environment. We compared their immunogenicity with the immunogenicity of the same antigens delivered with adenovirus 5-based vaccine vector. We now are proposing extending the testing to all six ZIKV recombinant subunit vaccines generated. The immunogenicity of these six subunit vaccines, named ZIKV-rE, ZIKV-rEDIII, ZIKV-rEhIg, ZIKV-rEDIIIhIg, ZIKV-rEfl, and ZIKV-rEDIIIfl, delivered via MNA, will be compared in C57B6 mice. Once the best performing ZIKV subunit vaccine is selected, the beneficial effect of adjuvant will be evaluated. Ultimately, we will test the efficacy of the selected subunit vaccine in a ZIKV surrogate animal challenge model. We hypothesize that administration of ZIKV subunit vaccines in a prime/boost regimen will elicit ZIKV-specific immunity that will lead to the effective immunization of pregnant mice with passage of passive immunity to newborns, which will be protected by ZIKV challenge.

抽象的 自从迅速从巴西传播后，2015年5月在美洲首次发现以来 病毒（ZIKV）引起了全球关注。巴西的Zikv爆发也与 出生的小头畸形和神经系统疾病（例如guillain-）的婴儿数量显着增加 Barré综合征已被世界卫生组织宣布为“全球紧急事件”。寨卡病毒是 与粉丝，黄热病，日本脑炎和西尼罗河病毒有关，所有这些都是节肢动物传播的 黄病毒。以文献中报告的成功黄病毒疫苗方法为基础，作为初步尝试 为了开发寨卡病毒疫苗，我们已经生成了基于重组Zika病毒亚基疫苗的小组 在ZIKV包膜基因的细胞外部分或ZIKV包膜基因的EDIII结构域上。这 黄病毒信封基因的EDIII环是接收器结合域，已被证明是最多的 抗病毒中和免疫力的有希望的靶标。这两种抗原（E和EDIII）都是生成的 单体（zikv-re和zikv-redii），作为与人IgG1的FC部分融合的二聚体（Zikv-Rehig 和zikv-rediiihig），以及与T4纤维蛋白折叠蛋白三聚化域（zikv-refl和 zikv-rediifl）。在此处介绍的初步研究中，我们测试了三聚Zikv-Refl的免疫原性 zikv-rediifl使用可溶解的微针阵列（MNA）递送系统经态交付 C57BL6小鼠。基于MNA的抗原输送系统的选择是合理的，因为它的效率和 简单且易于适应低卫生和纯社会经济环境。我们比较了他们 具有腺病毒5基疫苗的相同抗原的免疫原性的免疫原性 向量。现在，我们提议将测试扩展到产生的所有六个ZIKV重组亚基疫苗。 这六种亚基疫苗的免疫原性，名为Zikv-Re，Zikv-Rediii，Zikv-Rehig，Zikv-Readiiihig， 通过MNA传递的Zikv-Refl和Zikv-Rediifl将在C57B6小鼠中进行比较。曾经表现最好 选择了ZIKV亚基疫苗，将评估调整的有益效果。最终，我们将测试 ZIKV替代动物挑战模型中所选亚基疫苗的功效。我们假设这一点 在素数/增强方案中给予ZIKV亚基疫苗将引起ZIKV特异性免疫力 通过对新生儿的被动免疫的有效免疫免疫，这将是 受ZIKV挑战的保护。