Virus-like Particles Containing Multiple M2 Extracellular Domains Confer Improved Cross-protection Against Various Subtypes of Influenza Virus
Virus-like Particles Containing Multiple M2 Extracellular Domains Confer Improved Cross-protection Against Various Subtypes of Influenza Virus
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DOI：
10.1038/mt.2012.246
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发表时间：
2013-02-01
影响因子：
12.4
通讯作者：
Kang, Sang-Moo
中科院分区：
文献类型：
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作者：
Kim, Min-Chul;Song, Jae-Min;Kang, Sang-Moo
M2 (M2e) 是一种小离子通道膜蛋白，其胞外结构域在不同的人类甲型流感病毒株中高度保守。为了提高 M2e 疫苗的保护功效，我们对人、猪和禽类甲型流感病毒的 M2e 表位序列 (M2e5x) 进行了基因工程改造，该序列以膜锚定形式表达并掺入病毒样颗粒 (VLP) 中。具有血凝素 (HA) 跨膜结构域的 M2e5x 蛋白被有效地整合到 VLP 中，其水平比流感病毒颗粒高数百倍。在没有佐剂的情况下，无论流感病毒亚型如何，M2e5x VLP 疫苗的肌内免疫在诱导对不同流感病毒有反应的 M2e 特异性抗体、粘膜和全身免疫反应以及交叉保护方面非常有效。重要的是，发现免疫血清足以为幼鼠提供保护，这种保护是长寿命和交叉保护的。因此，分子设计和在 VLP 上呈现 M2e 免疫原为开发不使用佐剂的通用流感疫苗提供了一个有前景的平台。
The extracellular domain of M2 (M2e), a small ion channel membrane protein, is well conserved among different human influenza A virus strains. To improve the protective efficacy of M2e vaccines, we genetically engineered a tandem repeat of M2e epitope sequences (M2e5x) of human, swine, and avian origin influenza A viruses, which was expressed in a membrane-anchored form and incorporated in virus-like particles (VLPs). The M2e5x protein with the transmembrane domain of hemagglutinin (HA) was effectively incorporated into VLPs at a several 100-fold higher level than that on influenza virions. Intramuscular immunization with M2e5x VLP vaccines was highly effective in inducing M2e-specific antibodies reactive to different influenza viruses, mucosal and systemic immune responses, and cross-protection regardless of influenza virus subtypes in the absence of adjuvant. Importantly, immune sera were found to be sufficient for conferring protection in naive mice, which was long-lived and cross-protective. Thus, molecular designing and presenting M2e immunogens on VLPs provide a promising platform for developing universal influenza vaccines without using adjuvants.