A humanized mouse model identifies key amino acids for low immunogenicity of H7N9 vaccines.
A humanized mouse model identifies key amino acids for low immunogenicity of H7N9 vaccines.
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DOI：
10.1038/s41598-017-01372-5
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发表时间：
2017-04-28
影响因子：
4.6
通讯作者：
Takahashi Y
中科院分区：
文献类型：
--
作者：
Wada Y;Nithichanon A;Nobusawa E;Moise L;Martin WD;Yamamoto N;Terahara K;Hagiwara H;Odagiri T;Tashiro M;Lertmemongkolchai G;Takeyama H;De Groot AS;Ato M;Takahashi Y
H7N9亚型的流感疫苗在人类中的免疫原性始终低于为其他亚型开发的疫苗。尽管先前的免疫信息学分析鉴定了H7血凝素（HA）中的T细胞表位，其由于与人类基因组的保守性而潜在地增强调节性T细胞应答，但是由于缺乏再现在人类中观察到的应答的动物模型，T细胞表位与H7 HA的低免疫原性之间的联系仍然未知。在此，我们利用人源化小鼠模型来概括H7 HA的低免疫原性。我们的分析表明，通过改变3个氨基酸修饰单个H7表位，使其与已知的H3免疫原性表位序列同源，显著改善了人源化小鼠模型中H7 HA的免疫原性，导致HA结合IgG应答增加超过4倍。因此，我们提供了实验证据，这H7特异性T细胞表位在确定流感疫苗的免疫原性的重要贡献。此外，本研究描绘了可用于使用免疫信息学工具和人源化小鼠模型筛选和选择疫苗株的策略。
Influenza vaccines of H7N9 subtype are consistently less immunogenic in humans than vaccines developed for other subtypes. Although prior immunoinformatic analysis identified T-cell epitopes in H7 hemagglutinin (HA) which potentially enhance regulatory T cell response due to conservation with the human genome, the links between the T-cell epitopes and low immunogenicity of H7 HA remains unknown due to the lack of animal models reproducing the response observed in humans. Here, we utilized a humanized mouse model to recapitulate the low immunogenicity of H7 HA. Our analysis demonstrated that modification of a single H7 epitope by changing 3 amino acids so that it is homologous with a known H3 immunogenic epitope sequence significantly improved the immunogenicity of the H7 HA in the humanized mouse model, leading to a greater than 4-fold increase in HA-binding IgG responses. Thus, we provide experimental evidence for the important contribution of this H7-specific T cell epitope in determining the immunogenicity of an influenza vaccine. Furthermore, this study delineates strategies that can be used for screening and selecting vaccine strains using immunoinformatics tools and a humanized mouse model.