Vasilev Kirill, Puente-Massaguer Eduard, Hoxie Irene, Bushfield Kaitlyn, Krammer Florian
Department of Microbiology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA; Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA; Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Medical University of Vienna, Vienna, Austria.
Vaccine. 2025 Sep 17;63:127626. doi: 10.1016/j.vaccine.2025.127626. Epub 2025 Aug 27.
Chimeric hemagglutinin (cHA)-based vaccines represent a promising strategy toward the development of a broadly protective universal influenza virus vaccine. Previous studies show that sequential administration of cHA split influenza vaccines stimulates broadly cross-reactive antibodies targeting the HA stalk and induces systemic and localized CD4 T-cell responses to the HA, neuraminidase (NA), and nucleoprotein (NP). However, the exact role of the T-cellular immune response in the protection after vaccination with cHA constructs remains underinvestigated. Here we provide an in-depth characterization of the innate immune response and antigen-specific T-cellular immune response in mice after sequential immunization with the group 2 cH15/3N2 and cH4/3N2 virus vaccine candidates with or without CpG 1018 adjuvant and during a heterologous virus challenge. The non-adjuvanted split vaccine induced mixed Th1/Th2 T-cellular immune response associated with interferon-γ, interleukin (IL)-2, tumor necrosis factor α, IL-4, IL-5, IL-13, and IL-10 production whereas the adjuvanted vaccine (split/CpG) induced a Th1-polarized T-cellular immune response mediated by IL2TNFα and IFNγIL2TNFα polyfunctional CD4 effector memory T-lymphocytes. An increase in the Th2-associated cytokines (IL-4, IL-5, IL-13) and the eosinophil accumulation was shown in the lungs of mice immunized with a non-adjuvanted split vaccine after a challenge with a phylogenetically distant influenza virus. We also investigated the ability of T-cells to induce protection against the heterologous virus challenge in passive-transfer and T-cell depletion experiments. Passive transfer of sera from mice immunized with split/CpG vaccine reduced weight loss, inflammatory cytokine production, and viral replication in lungs after challenge. Passive transfer of T-cells from immunized to naïve mice did not reduce weight loss and viral replication but affected the innate immune cell population dynamics and cytokine response in mouse lungs after the challenge. The depletion of CD4 T-cells did not affect viral replication in mouse lungs but influenced cytokine production and innate immune cell population dynamics.
基于嵌合血凝素（cHA）的疫苗是开发具有广泛保护性的通用流感病毒疫苗的一种有前景的策略。先前的研究表明，序贯接种cHA裂解流感疫苗可刺激针对HA茎部的广泛交叉反应性抗体，并诱导对HA、神经氨酸酶（NA）和核蛋白（NP）的全身和局部CD4 T细胞反应。然而，在用cHA构建体接种疫苗后，T细胞免疫反应在保护中的具体作用仍未得到充分研究。在这里，我们深入表征了在接种或未接种CpG 1018佐剂的情况下，用2组cH15/3N2和cH4/3N2病毒候选疫苗序贯免疫小鼠后以及在异源病毒攻击期间的先天免疫反应和抗原特异性T细胞免疫反应。未加佐剂的裂解疫苗诱导了与干扰素-γ、白细胞介素（IL）-2、肿瘤坏死因子α、IL-4、IL-5、IL-13和IL-10产生相关的混合Th1/Th2 T细胞免疫反应，而加佐剂的疫苗（裂解/CpG）诱导了由IL2TNFα和IFNγIL2TNFα多功能CD4效应记忆T淋巴细胞介导的Th1极化T细胞免疫反应。在用系统发育上遥远的流感病毒攻击后，用未加佐剂的裂解疫苗免疫的小鼠肺部显示出Th2相关细胞因子（IL-4、IL-5、IL-13）增加和嗜酸性粒细胞积累。我们还在被动转移和T细胞耗竭实验中研究了T细胞诱导针对异源病毒攻击的保护能力。用裂解/CpG疫苗免疫的小鼠血清的被动转移减少了攻击后肺部的体重减轻、炎性细胞因子产生和病毒复制。将免疫小鼠的T细胞被动转移到未免疫小鼠中并没有减轻体重减轻和病毒复制，但影响了攻击后小鼠肺部先天免疫细胞群体动态和细胞因子反应。CD4 T细胞的耗竭并没有影响小鼠肺部的病毒复制，但影响了细胞因子产生和先天免疫细胞群体动态。
