A Novel Vaccine Strategy to Overcome Poor Immunogenicity of Avian Influenza Vaccines through Mobilization of Memory CD4 T Cells Established by Seasonal Influenza
A Novel Vaccine Strategy to Overcome Poor Immunogenicity of Avian Influenza Vaccines through Mobilization of Memory CD4 T Cells Established by Seasonal Influenza
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DOI：
10.4049/jimmunol.1900819
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发表时间：
2019-09-15
影响因子：
4.4
通讯作者：
Sant, Andrea J.
中科院分区：
文献类型：
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作者：
DiPiazza, Anthony T.;Fang, Shufang;Sant, Andrea J.
禽流感疫苗在人体内表现出较差的免疫原性。我们假设弱B细胞反应的一个因素是禽流感和季节性流感血凝素蛋白之间的序列差异，从而限制了CD4 T细胞帮助的可用性。为了验证这一点，我们获得了一种新的嵌合血凝素蛋白（cH7/3），该蛋白由来自季节性H3血凝素的茎结构域和来自禽类H7的头结构域组成。通过包括季节性灭活疫苗、Flumist和从H3茎结构域衍生的合成肽在内的策略，在小鼠中建立了对季节性流感的免疫记忆。小鼠建立记忆后，分别接种H7或cH7/3蛋白。cH7/3 Ag能够召回h3特异性CD4 T细胞，这种增强的CD4 T细胞反应与增强的早期生发中心反应和对H7抗体的快速激发有关，包括H7头部结构域特异性的抗体。这些结果表明，在大流行的情况下，包含来自季节性病毒的CD4 T细胞表位有可能通过帮助B细胞和赋予病毒HA更大的亚型特异性Ab反应来克服禽疫苗的免疫原性差。
Avian influenza vaccines exhibit poor immunogenicity in humans. We hypothesized that one factor underlying weak B cell responses was sequence divergence between avian and seasonal influenza hemagglutinin proteins, thus limiting the availability of adequate CD4 T cell help. To test this, a novel chimeric hemagglutinin protein (cH7/3) was derived, comprised of the stem domain from seasonal H3 hemagglutinin and the head domain from avian H7. Immunological memory to seasonal influenza was established in mice, through strategies that included seasonal inactivated vaccines, Flumist, and synthetic peptides derived from the H3 stalk domain. After establishment of memory, mice were vaccinated with H7 or cH7/3 protein. The cH7/3 Ag was able to recall H3-specific CD4 T cells, and this potentiated CD4 T cell response was associated with enhanced early germinal center response and rapid elicitation of Abs to H7, including Abs specific for the H7 head domain. These results suggest that in pandemic situations, inclusion of CD4 T cell epitopes from seasonal viruses have the potential to overcome the poor immunogenicity of avian vaccines by helping B cells and conferring greater subtype-specific Ab response to viral HA.