Novel H7N9 influenza immunogen design enhances mobilization of seasonal influenza T cell memory in H3N2 pre-immune mice.
Novel H7N9 influenza immunogen design enhances mobilization of seasonal influenza T cell memory in H3N2 pre-immune mice.
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DOI：
10.1080/21645515.2022.2082191
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发表时间：
2022-11-30
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
提高流感疫苗免疫原性的策略对于开发大流行防备疫苗至关重要。血凝素（HA）特异性CD 4 + T细胞表位支持针对季节性流感的保护性B细胞应答。然而，在造成大流行威胁的禽类H7N9的情况下，HA在没有佐剂的情况下在感染和疫苗接种中仅引起弱的中和抗体应答。我们假设，免疫工程化的H7 N9 HA包含广泛反应性的H3 N2 HA特异性记忆CD 4 + T细胞表位，该表位取代了H7 N9 HA相应位置的调节性T细胞诱导表位，可以利用预先存在的流感T细胞免疫力来增加CD 4+保护性抗体发展所需的T细胞。我们设计并制备了携带表位增强的H7N9 HA（OPT 1）的病毒样颗粒（VLP）疫苗，并免疫具有已建立的H3 N2免疫力的HLA-DR 3转基因小鼠。与野生型VLP免疫相比，OPT 1-VLP刺激更高的干细胞、中枢和效应记忆CD 4 + T细胞水平。此外，激活，IL-21产生滤泡辅助T细胞的频率增加。这种新的免疫原设计策略表明，旨在增加T细胞表位含量的位点特异性修饰增强了关键亚群中的CD 4 + T细胞应答，这些亚群能够在抗原重新相遇时帮助保护性免疫应答，并且免疫记忆的动员可用于克服禽流感病毒的免疫原性差。
Strategies that improve influenza vaccine immunogenicity are critical for the development of vaccines for pandemic preparedness. Hemagglutinin (HA)-specific CD4+ T cell epitopes support protective B cell responses against seasonal influenza. However, in the case of avian H7N9, which poses a pandemic threat, HA elicits only weak neutralizing antibody responses in infection and vaccination without adjuvant. We hypothesized that an immune-engineered H7N9 HA incorporating a broadly reactive H3N2 HA-specific memory CD4+ T cell epitope that replaces a regulatory T cell-inducing epitope at the corresponding position in H7N9 HA could harness preexisting influenza T cell immunity to increase CD4+ T cells that are needed for protective antibody development. We designed and produced a virus-like particle (VLP) vaccine that carries the epitope augmented H7N9 HA (OPT1) and immunized HLA-DR3 transgenic mice with established H3N2 immunity. OPT1-VLPs stimulated higher stem cell, central, and effector memory CD4+ T cell levels over wild type VLP immunization. In addition, activated, IL-21-producing follicular helper T cell frequencies were enhanced. This novel immunogen design strategy illustrates that site-specific modifications aimed to augment T cell epitope content enhance CD4+ T cell responses among critical subpopulations capable of aiding protective immune responses upon antigen re-encounter and that mobilization of immune memory can be used to overcome the poor immunogenicity of avian influenza viruses.
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