腺病毒作為疫苗載體,，具有宿主范圍廣,、對(duì)人致病性低，與人類基因同源,，能有效進(jìn)行增殖,、滴度高等優(yōu)點(diǎn)，是目前最有應(yīng)用前景的新型疫苗載體之一,。
上海巴斯德所抗感染免疫與疫苗研究組在周東明研究員的帶領(lǐng)下,，致力于新型疫苗載體、通用型流感疫苗的研發(fā)及相關(guān)免疫學(xué)研究,。近日,，他們與Wistar研究所研究人員對(duì)腺病毒作為疫苗載體開展的合作研究取得了新進(jìn)展，研究成果以Hexon-modified Recombinant E1-deleted Adenovirus Vectors as Dual Specificity Vaccine Carriers for Influenza Virus為題,，在線發(fā)表于國(guó)際學(xué)術(shù)期刊《分子治療》（Molecular Therapy）,。
研究中，他們以E1缺失的黑猩猩型腺病毒AdC68載體為基礎(chǔ),，將流感病毒H1N1的M2e基因克隆至Hexon R1或R4區(qū),，同時(shí)將H1N1，H5N1以及H7N2的三種M2e基因以及H1N1的NP基因聯(lián)合克隆于Hexon經(jīng)改造后的新型腺病毒載體的E1缺失區(qū),，獲得在Hexon可變區(qū)及E1缺失區(qū)同時(shí)表達(dá)外源基因的多種重組腺病毒,。免疫動(dòng)物后發(fā)現(xiàn)，Hexon R1經(jīng)改造后的雙表達(dá)載體可誘導(dǎo)高強(qiáng)度,、高親和力的特異性抗體,，并對(duì)致死劑量的流感病毒攻擊感染產(chǎn)生良好的免疫保護(hù)效果；Hexon R4經(jīng)改造后的雙表達(dá)載體的免疫效果則相對(duì)低下,。
該項(xiàng)研究深入闡明了腺病毒新的生物學(xué),、免疫學(xué)特性，進(jìn)一步優(yōu)化了腺病毒載體,，對(duì)于新型疫苗載體的設(shè)計(jì)與評(píng)價(jià)具有重要指導(dǎo)性意義,，同時(shí)也為新型通用型流感疫苗的研制提供了一種新策略,。
該項(xiàng)研究獲得了國(guó)家自然科學(xué)基金面上項(xiàng)目、美國(guó)NIH,、賓州政府等多項(xiàng)經(jīng)費(fèi)支持,。(生物谷Bioon.com)
doi:10.1038/mt.2012.248
PMC:
PMID:
Hexon-modified Recombinant E1-deleted Adenovirus Vectors as Dual Specificity Vaccine Carriers for Influenza Virus
Dongming Zhou, Te-Lang Wu, Kristel L Emmer, Raj Kurupati, Steven Tuyishime, Yan Li, Wynetta Giles-Davis, Xiangyang Zhou, Zhiquan Xiang, Qin Liu, Sarah J Ratcliffe and Hildegund CJ Ertl
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.
