Mol.Ther.：上海巴斯德所在新型疫苗载体合作研究中取得新进展

腺病毒作为疫苗载体，具有宿主范围广、对人致病性低，与人类基因同源，能有效进行增殖、滴度高等优点，是目前最有应用前景的新型疫苗载体之一。

上海巴斯德所抗感染免疫与疫苗研究组在周东明研究员的带领下，致力于新型疫苗载体、通用型流感疫苗的研发及相关免疫学研究。近日，他们与Wistar研究所研究人员对腺病毒作为疫苗载体开展的合作研究取得了新进展，研究成果以Hexon-modified Recombinant E1-deleted Adenovirus Vectors as Dual Specificity Vaccine Carriers for Influenza Virus为题，在线发表于国际知名学术期刊《分子治疗》（Molecular Therapy）。

研究中，他们以E1缺失的黑猩猩型腺病毒AdC68载体为基础，将流感病毒H1N1的M2e基因克隆至Hexon R1或R4区，同时将H1N1，H5N1以及H7N2的三种M2e基因以及H1N1的NP基因联合克隆于Hexon经改造后的新型腺病毒载体的E1缺失区，获得在Hexon可变区及E1缺失区同时表达外源基因的多种重组腺病毒。免疫动物后发现，Hexon R1经改造后的双表达载体可诱导高强度、高亲和力的特异性抗体，并对致死剂量的流感病毒攻击感染产生良好的免疫保护效果；Hexon R4经改造后的双表达载体的免疫效果则相对低下。

该项研究深入阐明了腺病毒新的生物学、免疫学特性，进一步优化了腺病毒载体，对于新型疫苗载体的设计与评价具有重要指导性意义，同时也为新型通用型流感疫苗的研制提供了一种新策略。

该项研究获得了国家自然科学基金面上项目、美国NIH、宾州政府等多项经费支持

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Hexon-modified recombinant E1-deleted adenovirus vectors as dual specificity vaccine carriers for influenza virus.
Abstract
To determine if an ordered and repetitive display of an epitope promoted induction of superior antibody responses, we compared B-cell responses to an influenza A virus epitope that was either encoded as a transgene by an adenovirus (Ad) vector or expressed on the vector's surface. To this end, we constructed a panel of influenza A virus vaccines based on chimpanzee-derived replication-defective adenovirus (AdC) vectors of serotype SAd-V25 also called AdC68. AdC68 vectors were modified to express a linear B-cell epitope of the ectodomain of matrix 2 (M2e) within variable regions 1 (VR1) or 4 (VR4) of the adenovirus hexon. Additional vectors with wild-type or M2e-modified hexon encoded M2e fused to the influenza A virus nucleoprotein (NP) as a transgene product. Hexon-modified vectors were tested for immunogenicity and efficacy in mice in comparison to vectors with native hexon expressing the M2e-NP fusion protein. Upon priming, vectors expressing M2e within VR1 of hexon induced M2e-specific antibody responses of higher magnitude and avidity than those carrying M2e within VR4 or vectors expressing the M2e as part of a transgene product. CD8(+) T-cell responses to the transgenic NP were comparable between vectors. M2e-specific antibody responses could be boosted by a second dose of the VR1 hexon-modified vector but not by repeated immunization with the VR4 hexon-modified vector.