Targeting the HA2 subunit of influenza A virus hemagglutinin via CD40L provides universal protection against diverse subtypes.
Targeting the HA2 subunit of influenza A virus hemagglutinin via CD40L provides universal protection against diverse subtypes.
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流感病毒血凝素 (HA) 由两个亚基组成。目前的流感疫苗主要诱导针对 HA1 亚基的中和抗体 (Ab)，该亚基以不可预测的方式不断进化。然而，另一个亚基 HA2 高度保守，但很大程度上被 HA 头结构域屏蔽。因此，增强针对 HA2 的免疫反应可能会引发广泛的抑制性抗体。我们生成了编码分泌融合蛋白的重组腺病毒（rAd），该蛋白由密码子优化的甲型流感/加利福尼亚/7/2009（H1N1）流感病毒HA2亚基与鼠CD40L三聚体融合组成，并确定了其鼻内给药后诱导保护性免疫的能力。我们发现，用这种重组病毒疫苗免疫的小鼠可以完全免受不同甲型流感病毒亚型（包括 H1N1、H3N2 和 H9N2）的致命攻击。 HA2 的密码子优化以及使用 CD40L 作为靶向配体/分子佐剂对于增强 HA2 特异性粘膜 IgA 和血清 IgG 水平是必不可少的。此外，HA2特异性T细胞反应的诱导依赖于CD40L，因为在没有CD40L的情况下分泌HA2亚基的rAd不能诱导任何显着水平的T细胞细胞因子。最后，从免疫小鼠获得的血清能够在体外抑制 13 种甲型流感病毒亚型。这些结果为基于 HA2 的通用流感疫苗原型提供了概念证明。
The influenza viral hemagglutinin (HA) is comprised of two subunits. Current influenza vaccine predominantly induces neutralizing antibodies (Abs) against the HA1 subunit, which is constantly evolving in unpredictable fashion. The other subunit, HA2, however, is highly conserved but largely shielded by the HA head domain. Thus, enhancing immune response against HA2 could potentially elicit broadly inhibitory Abs. We generated a recombinant adenovirus (rAd) encoding secreted fusion protein, consisting of codon-optimized HA2 subunit of influenza A/California/7/2009(H1N1) virus fused to a trimerized form of murine CD40L, and determined its ability of inducing protective immunity upon intranasal administration. We found that mice immunized with this recombinant viral vaccine were completely protected against lethal challenge with divergent influenza A virus subtypes including H1N1, H3N2, and H9N2. Codon-optimization of HA2 as well as the use of CD40L as a targeting ligand/molecular adjuvant were indispensable to enhance HA2-specific mucosal IgA and serum IgG levels. Moreover, induction of HA2-specific T-cell responses was dependent on CD40L, as rAd secreting HA2 subunit without CD40L failed to induce any significant levels of T-cell cytokines. Finally, sera obtained from immunized mice were capable of inhibiting 13 subtypes of influenza A viruses in vitro. These results provide proof of concept for a prototype HA2-based universal influenza vaccine.
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