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 2015 年 5 月在美洲首次发现并从巴西迅速传播以来，由蚊子传播的寨卡病毒 巴西寨卡病毒（ZIKV）的爆发也引起了全球的关注。 出生时患有小头畸形和神经系统疾病（例如格林- 巴雷综合症已被世界卫生组织宣布为“全球紧急状态”。 与登革热、黄热病、日本脑炎和西尼罗河病毒有关，所有这些病毒都是节肢动物传播的 以文献中报道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，我们开发了一组重组寨卡病毒亚单位疫苗 ZIKV 包膜基因的细胞外部分或 ZIKV 包膜基因的 EDIII 结构域。 黄病毒包膜基因的 EDIII 环是受体结合域，已被证明是最 这两种抗原（E 和 EDIII）都是作为抗病毒中和免疫的有希望的靶标。 单体（ZIKV-rE 和 ZIKV-rEDIII），作为与人 IgG1 的 fc 部分融合的二聚体（ZIKV-rEhIg 和 ZIKV-rEDIIIhIg），以及与 T4 fibritin 折叠三聚化结构域融合的三聚体（ZIKV-rEfl 和 ZIKV-rEDIIIfl)。在此介绍的初步研究中，我们测试了三聚体 ZIKV-rEfl 的免疫原性。 ZIKV-rEDIIIfl 使用可溶性微针阵列 (MNA) 递送系统经皮递送至 C57BL6 小鼠选择基于 MNA 的抗原递送系统是合理的，因为它的功效和作用。 简单且易于适应在低卫生条件和纯净的社会经济环境中使用我们对它们进行了比较。 与基于腺病毒 5 的疫苗递送的相同抗原具有免疫原性 我们现在提议将测试范围扩大到所有六种 ZIKV 重组亚单位疫苗。 这六种亚单位疫苗的免疫原性，分别命名为ZIKV-rE、ZIKV-rEDIII、ZIKV-rEhIg、ZIKV-rEDIIIhIg、 通过 MNA 递送的 ZIKV-rEfl 和 ZIKV-rEDIIIfl 将在 C57B6 小鼠中进行比较，一旦表现最佳。 选择ZIKV亚单位疫苗后，将评估佐剂的有益效果，最终我们将对其进行测试。 所选亚单位疫苗在 ZIKV 替代动物攻击模型中的功效。 在初免/加强方案中施用 ZIKV 亚单位疫苗将引发 ZIKV 特异性免疫，从而导致 对怀孕小鼠进行有效免疫，并将被动免疫传递给新生小鼠，这将是 受到 ZIKV 挑战的保护。