Improved design and intranasal delivery of an M2e-based human influenza A vaccine
Improved design and intranasal delivery of an M2e-based human influenza A vaccine
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DOI：
10.1016/j.vaccine.2006.05.082
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发表时间：
2006-11-10
期刊：
影响因子：
5.5
通讯作者：
Saelens, Xavier
中科院分区：
文献类型：
--
作者：
De Filette, Marina;Fiers, Walter;Saelens, Xavier
M2是甲型流感病毒的第三种膜蛋白。M2 e是M2的胞外23个氨基酸残基，在所有人甲型流感病毒株中均显著保守。这促使我们在流感感染的小鼠模型中评估M2 e作为潜在广谱免疫原的用途。M2 e和B型肝炎病毒核心（HBc）编码序列的基因融合使我们能够获得高度免疫原性的病毒样颗粒。该M2 e-HBe疫苗在小鼠中诱导针对致死性流感攻击的完全保护。无论M2 e在M2 e-HBc嵌合体中的位置是在氨基末端还是插入HBc蛋白的免疫显性环中，都获得了保护性免疫。将插入N端的M2 e拷贝数从每个单体1个增加到3个（每个颗粒240-720个），显著增强了免疫应答，并减少了完全保护免受甲型流感病毒致命攻击所需的疫苗接种次数。随后将一系列M2 e-HBc构建体与CTA 1-DD（一种重组霍乱毒素A1衍生的粘膜佐剂）组合，以测试其作为鼻内递送疫苗的功效。用CTA 1-DD测试的所有杂交VLP完全保护小鼠免受潜在的致死性感染，此外，显著降低发病率。总体而言，小鼠对流感攻击的抵抗力增加与疫苗接种诱导的Th 1型M2 e特异性抗体应答增强相关。这些结果表明，我们是一种有效的和多功能的候选疫苗，以保护免受任何人流感A毒株。(c)2006爱思唯尔有限公司保留所有权利。
M2 is the third integral membrane protein of influenza A. M2e, the extracellular, 23 amino acid residues of M2, has been remarkably conserved in all human influenza A strains. This prompted us to evaluate the use of M2e as a potential broad-spectrum immunogen in a mouse model for influenza infection. Genetic fusion of the M2e and hepatitis B virus core (HBc) coding sequences allowed us to obtain highly immunogenic virus-like particles. This M2e-HBe vaccine induced complete protection in mice against a lethal influenza challenge. Protective immunity was obtained regardless of the position of M2e in the M2e-HBc chimera at the amino-terminus or inserted in the immuno-dominant loop of the HBc protein. Increasing the copy number of M2e inserted at the N-terminus from one to three per monomer (240-720 per particle) significantly enhanced the immune response and reduced the number of vaccinations required for complete protection against a lethal challenge with influenza A virus. A series of M2e-HBc constructs was subsequently combined with CTA1-DD, a recombinant cholera toxin A1 derived mucosal adjuvant, to test its efficacy as an intranasally delivered vaccine. All hybrid VLPs tested with CTA1-DD completely protected mice from a potentially lethal infection and, in addition, significantly reduced morbidity. Overall, increased resistance to influenza challenge in the mice correlated with an enhanced Th1-type M2e-specific antibody response induced by vaccination. These results show that We is a valid and versatile vaccine candidate to protect against any strain of human influenza A. (c) 2006 Elsevier Ltd. All rights reserved.