Institute for Infection and Immunity, St George's University of London, London, UK.
Department of Molecular Biology and the Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju, Korea.
Plant Biotechnol J. 2018 Jul;16(7):1283-1294. doi: 10.1111/pbi.12869. Epub 2018 Feb 1.
Dengue is a major global disease requiring improved treatment and prevention strategies. The recently licensed Sanofi Pasteur Dengvaxia vaccine does not protect children under the age of nine, and additional vaccine strategies are thus needed to halt this expanding global epidemic. Here, we employed a molecular engineering approach and plant expression to produce a humanized and highly immunogenic poly-immunoglobulin G scaffold (PIGS) fused to the consensus dengue envelope protein III domain (cEDIII). The immunogenicity of this IgG Fc receptor-targeted vaccine candidate was demonstrated in transgenic mice expressing human FcγRI/CD64, by induction of neutralizing antibodies and evidence of cell-mediated immunity. Furthermore, these molecules were able to prime immune cells from human adenoid/tonsillar tissue ex vivo as evidenced by antigen-specific CD4 and CD8 T-cell proliferation, IFN-γ and antibody production. The purified polymeric fraction of dengue PIGS (D-PIGS) induced stronger immune activation than the monomeric form, suggesting a more efficient interaction with the low-affinity Fcγ receptors on antigen-presenting cells. These results show that the plant-expressed D-PIGS have the potential for translation towards a safe and easily scalable single antigen-based tetravalent dengue vaccine.
登革热是一种全球性的主要疾病，需要改进治疗和预防策略。最近获得许可的赛诺菲巴斯德登革热疫苗不能保护 9 岁以下的儿童，因此需要额外的疫苗策略来阻止这种不断扩大的全球流行。在这里，我们采用分子工程方法和植物表达生产了一种人源化的、高度免疫原性的多免疫球蛋白 G 支架（PIGS），与登革热包膜蛋白 III 结构域的共识序列（cEDIII）融合。在表达人 FcγRI/CD64 的转基因小鼠中，通过诱导中和抗体和细胞介导免疫的证据，证明了这种 IgG Fc 受体靶向疫苗候选物的免疫原性。此外，这些分子能够从人腺样体/扁桃体组织中体外刺激免疫细胞，表现为抗原特异性 CD4 和 CD8 T 细胞增殖、IFN-γ 和抗体产生。纯化的登革热 PIGS（D-PIGS）多聚体比单体形式诱导更强的免疫激活，这表明它与抗原呈递细胞上的低亲和力 Fcγ 受体的相互作用更有效。这些结果表明，植物表达的 D-PIGS 有可能转化为一种安全且易于规模化的单价四价登革热疫苗。
