基于活减嵌合血凝素疫苗的序贯免疫在临床前雪貂模型中诱导针对甲型流感病毒的异源型免疫。

Sequential Immunization With Live-Attenuated Chimeric Hemagglutinin-Based Vaccines Confers Heterosubtypic Immunity Against Influenza A Viruses in a Preclinical Ferret Model.

机构信息

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

出版信息

Front Immunol. 2019 Apr 10;10:756. doi: 10.3389/fimmu.2019.00756. eCollection 2019.

Abstract

Due to continuous antigenic drift and occasional antigenic shift, influenza viruses escape from human adaptive immunity resulting in significant morbidity and mortality in humans. Therefore, to avoid the need for annual reformulation and readministration of seasonal influenza virus vaccines, we are developing a novel chimeric hemagglutinin (cHA)-based universal influenza virus vaccine, which is comprised of sequential immunization with antigens containing a conserved stalk domain derived from a circulating pandemic H1N1 strain in combination with "exotic" head domains. Here, we show that this prime-boost sequential immunization strategy redirects antibody responses toward the conserved stalk region. We compared the vaccine efficacy elicited by distinct vaccination approaches in the preclinical ferret model of influenza. All ferrets immunized with cHA-based vaccines developed stalk-specific and broadly cross-reactive antibody responses. Two consecutive vaccinations with live-attenuated influenza viruses (LAIV-LAIV) conferred superior protection against pH1N1 and H6N1 challenge infection. Sequential immunization with LAIV followed by inactivated influenza vaccine (LAIV-IIV regimen) also induced robust antibody responses. Importantly, the LAIV-LAIV immunization regimen also induced HA stalk-specific CD4IFN-γ and CD8IFN-γ effector T cell responses in peripheral blood that were recalled by pH1N1 viral challenge. The findings from this preclinical study suggest that an LAIV-LAIV vaccination regimen would be more efficient in providing broadly protective immunity against influenza virus infection as compared to other approaches tested here.

摘要

由于抗原不断发生漂移和偶尔的抗原转变,流感病毒能够逃避人体适应性免疫,导致人类发病率和死亡率显著增加。因此,为了避免每年对季节性流感病毒疫苗进行重新配方和重新给药,我们正在开发一种新型嵌合血凝素 (cHA)-为基础的通用流感病毒疫苗,该疫苗由连续免疫用抗原组成,这些抗原包含源自循环大流行 H1N1 株的保守茎域,以及“外来”的头部结构域。在这里,我们表明这种初免-加强序贯免疫策略将抗体反应重定向到保守的茎区。我们比较了不同疫苗接种方法在流感的临床前雪貂模型中引发的疫苗效力。所有用基于 cHA 的疫苗免疫的雪貂均产生了针对茎的特异性和广泛交叉反应性抗体反应。用减毒活流感病毒(LAIV-LAIV)进行两次连续接种可提供针对 pH1N1 和 H6N1 挑战感染的更佳保护。用 LAIV 进行序贯免疫,然后用灭活流感疫苗(LAIV-IIV 方案)也可诱导出强大的抗体反应。重要的是,LAIV-LAIV 免疫方案还诱导了外周血中针对 HA 茎的特异性 CD4IFN-γ和 CD8IFN-γ效应 T 细胞反应,这些反应可被 pH1N1 病毒挑战所召回。这项临床前研究的结果表明,与这里测试的其他方法相比,LAIV-LAIV 免疫方案在提供针对流感病毒感染的广泛保护免疫方面更有效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dca1/6499175/e52b728782b4/fimmu-10-00756-g0001.jpg

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