Murine cross-reactive non-neutralizing polyclonal IgG1 antibodies induced by influenza vaccine inhibit the cross-protective effect of IgG2 against heterologous virus in mice.
Murine cross-reactive non-neutralizing polyclonal IgG1 antibodies induced by influenza vaccine inhibit the cross-protective effect of IgG2 against heterologous virus in mice.
复制标题
流感疫苗诱导的小鼠交叉反应性非中和性多克隆 IgG1 抗体可抑制小鼠体内 IgG2 对异源病毒的交叉保护作用。
DOI：
10.1128/jvi.00323-20
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Yoshioka Y.
中科院分区：
文献类型：
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作者：
Shibuya M;Aoshi T;Kuroda E;Yoshioka Y.
每年接种流感疫苗是预防和控制年度流行病和预防严重流感疾病的最可靠和有效的方法。然而，目前的裂解流感疫苗通常对抗原错配（异源）毒株无效。为了拓宽流感疫苗的保护谱，迫切需要能够通过Fc介导的效应子功能诱导具有交叉保护的交叉反应性抗体的佐剂。尽管IgG2抗体在Fc介导的效应子功能方面通常比IgG1抗体更有效，但目前尚不清楚哪些IgG同种型对异源菌株显示出上级的交叉保护作用。目前还不清楚这些IgG同种型是否会干扰彼此的保护作用。在这里，我们发现，以铝盐为佐剂的流感裂解疫苗，主要诱导交叉反应性IgG1，在小鼠中不赋予针对异源病毒攻击的交叉保护。相反，裂解疫苗佐剂与CpG寡脱氧核苷酸，主要诱导交叉反应性IgG 2，显示交叉保护通过交叉反应性非中和IgG 2和肺泡巨噬细胞的相互作用，表明交叉反应性非中和IgG 2的交叉保护的重要性。此外，通过使用免疫小鼠的血清样品和分离的多克隆抗体，我们表明，疫苗诱导的交叉反应性非中和性IgG1通过竞争性抑制IgG2与病毒的结合来抑制IgG2的交叉保护作用。因此，我们证明了新的概念，交叉反应IgG 1可能会干扰流感疫苗的交叉保护潜力。我们建议，佐剂，选择性地诱导病毒特异性IgG 2在小鼠中，如CpG寡脱氧核苷酸，是最佳的异源protection.IMPORTANCECurrent流感疫苗通常是有效的高度相似的病毒株诱导中和抗体。然而，这些抗体不能中和抗原错配（异源）菌株，因此提供有限的保护。目前正在努力开发具有交叉保护能力的疫苗，这些疫苗将广泛保护免受异源菌株的侵害，因为预测菌株和流行菌株之间的不匹配总是无法避免的，从而导致疫苗效力低下。在这里，我们表明，非中和IgG2抗体诱导的最佳佐剂在小鼠中对异源病毒的攻击交叉保护中发挥着至关重要的作用。此外，非中和性多克隆IgG1通过竞争性阻断IgG2与其抗原的结合而抑制非中和性多克隆IgG2的交叉保护作用。这些数据揭示了IgG同种型的重要性和选择合适的佐剂开发通用流感疫苗的新的光。此外，我们的研究结果适用于针对其他病原体的疫苗的合理设计。
Annual vaccination against influenza viruses is the most reliable and efficient way to prevent and control annual epidemics and protect from severe influenza disease. However, current split influenza vaccines are generally not effective against antigenically mismatched (heterologous) strains. To broaden the protective spectrum of influenza vaccines, adjuvants that can induce cross-reactive antibodies with cross-protection via Fc-mediated effector functions are urgently sought. Although IgG2 antibodies are generally more efficient than IgG1 antibodies in Fc-mediated effector functions, it is not yet clear which IgG isotypes show superior cross-protection against heterologous strains. It also remains unclear whether these IgG isotypes interfere with each other’s protective effects. Here, we found that influenza split vaccine adjuvanted with aluminum salts, which predominantly induce cross-reactive IgG1, did not confer cross-protection against heterologous virus challenge in mice. In contrast, split vaccine adjuvanted with CpG oligodeoxynucleotides, which predominantly induce cross-reactive IgG2, showed cross-protection through the interaction of cross-reactive nonneutralizing IgG2 and alveolar macrophages, indicating the importance of cross-reactive nonneutralizing IgG2 for cross-protection. Furthermore, by using serum samples from immunized mice and isolated polyclonal antibodies, we show that vaccine-induced cross-reactive nonneutralizing IgG1 suppress the cross-protective effects of IgG2 by competitively inhibiting the binding of IgG2 to virus. Thus, we demonstrate the new concept that cross-reactive IgG1 may interfere with the potential for cross-protection of influenza vaccine. We propose that adjuvants that selectively induce virus-specific IgG2 in mice, such as CpG oligodeoxynucleotides, are optimal for heterologous protection.IMPORTANCECurrent influenza vaccines are generally effective against highly similar virus strains by inducing neutralizing antibodies. However, these antibodies fail to neutralize antigenically mismatched (heterologous) strains and therefore provide limited protection against them. Efforts are being made to develop vaccines with cross-protective ability that would protect broadly against heterologous strains, because the mismatch between predicted and epidemic strains cannot always be avoided, resulting in low vaccine efficacy. Here, we show that nonneutralizing IgG2 antibodies induced by an optimal adjuvant play a crucial role in cross-protection against heterologous virus challenge in mice. Furthermore, nonneutralizing polyclonal IgG1 suppressed the cross-protective effects of nonneutralizing polyclonal IgG2 by competitively blocking the binding of IgG2 to its antigen. These data shed new light on the importance of IgG isotypes and the selection of appropriate adjuvants for the development of universal influenza vaccines. Furthermore, our findings are applicable to the rational design of vaccines against other pathogens.