Choi Angela, Bouzya Badiaa, Cortés Franco Klaus-Daniel, Stadlbauer Daniel, Rajabhathor Arvind, Rouxel Ronan N, Mainil Roland, Van der Wielen Marie, Palese Peter, García-Sastre Adolfo, Innis Bruce L, Krammer Florian, Schotsaert Michael, Mallett Corey P, Nachbagauer Raffael
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
GlaxoSmithKline, 1330 Rixensart, Belgium.
Immunohorizons. 2019 Apr 1;3(4):133-148. doi: 10.4049/immunohorizons.1900022.
The high variation of the influenza virus hemagglutinin (HA), particularly of its immunodominant head epitopes, makes it necessary to reformulate seasonal influenza virus vaccines every year. Novel influenza virus vaccines that redirect the immune response toward conserved epitopes of the HA stalk domain should afford broad and durable protection. Sequential immunization with chimeric HAs (cHAs) that express the same conserved HA stalk and distinct exotic HA heads has been shown to elicit high levels of broadly cross-reactive Abs. In the current mouse immunization studies, we tested this strategy using inactivated split virion cHA influenza virus vaccines (IIV) without adjuvant or adjuvanted with AS01 or AS03 to measure the impact of adjuvant on the Ab response. The vaccines elicited high levels of cross-reactive Abs that showed activity in an Ab-dependent, cell-mediated cytotoxicity reporter assay and were protective in a mouse viral challenge model after serum transfer. In addition, T cell responses to adjuvanted IIV were compared with responses to a cHA-expressing live attenuated influenza virus vaccine (LAIV). A strong but transient induction of Ag-specific T cells was observed in the spleens of mice vaccinated with LAIV. Interestingly, IIV also induced T cells, which were successfully recalled upon viral challenge. Groups that received AS01-adjuvanted IIV or LAIV 4 wk before the challenge showed the lowest level of viral replication (i.e., the highest level of protection). These studies provide evidence that broadly cross-reactive Abs elicited by cHA vaccination demonstrate Fc-mediated activity. In addition, cHA vaccination induced Ag-specific cellular responses that can contribute to protection upon infection.
流感病毒血凝素（HA），尤其是其免疫显性头部表位的高度变异性，使得每年都有必要重新配制季节性流感病毒疫苗。将免疫反应重定向至HA茎区保守表位的新型流感病毒疫苗应能提供广泛而持久的保护。用表达相同保守HA茎和不同外来HA头部的嵌合HA（cHA）进行序贯免疫已被证明可引发高水平的广泛交叉反应性抗体。在当前的小鼠免疫研究中，我们使用无佐剂或佐以AS01或AS03的灭活裂解病毒cHA流感病毒疫苗（IIV）来测试该策略，以测量佐剂对抗体反应的影响。这些疫苗引发了高水平的交叉反应性抗体，这些抗体在抗体依赖性细胞介导的细胞毒性报告试验中表现出活性，并且在血清转移后的小鼠病毒攻击模型中具有保护作用。此外，将佐剂化IIV的T细胞反应与表达cHA的减毒活流感病毒疫苗（LAIV）的反应进行了比较。在用LAIV免疫的小鼠脾脏中观察到了Ag特异性T细胞的强烈但短暂的诱导。有趣的是，IIV也诱导了T细胞，这些T细胞在病毒攻击时被成功召回。在攻击前4周接受AS01佐剂化IIV或LAIV的组显示出最低水平的病毒复制（即最高水平的保护）。这些研究提供了证据，表明cHA疫苗接种引发的广泛交叉反应性抗体表现出Fc介导的活性。此外，cHA疫苗接种诱导了Ag特异性细胞反应，这些反应可在感染时有助于提供保护。
