Generation and Characterization of Universal Live-Attenuated Influenza Vaccine Candidates Containing Multiple M2e Epitopes.
Generation and Characterization of Universal Live-Attenuated Influenza Vaccine Candidates Containing Multiple M2e Epitopes.
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DOI：
10.3390/vaccines8040648
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发表时间：
2020-11-03
期刊：
影响因子：
7.8
通讯作者：
Rudenko L
中科院分区：
文献类型：
--
作者：
Kotomina T;Isakova-Sivak I;Kim KH;Park BR;Jung YJ;Lee Y;Mezhenskaya D;Matyushenko V;Kang SM;Rudenko L
流感病毒不断进化，降低了常规疫苗接种活动的总体保护作用。目前正在探索许多不同的策略来设计能够保护免受进化分歧病毒的通用流感疫苗。甲型流感病毒M2 e蛋白（M2 e）的胞外域是通用疫苗设计的最有前途的靶标之一。在这里，我们产生了两种重组减毒活流感疫苗（LAIV）表达额外的四个M2 e串联重复序列（4 M2 e）从病毒血凝素（HA）蛋白的N-末端，试图提高M2 e介导的交叉保护。重组H1N1+ 4 M2 e和H3 N2 + 4 M2 e病毒保留了传统LAIV病毒的生长特性，并在BALB/c小鼠中诱导了强大的流感特异性抗体应答，尽管M2 e特异性抗体仅在用LAIV+4 M2 e病毒接种两次后才产生。用LAIV或LAIV+4 M2 e病毒免疫的小鼠完全保护免受一组异源流感攻击病毒的攻击，表明抗体和细胞介导的免疫有助于保护。在被动血清转移实验中观察到M2 e特异性抗体的保护作用，其中对于H3 N2和H5 N1异源攻击病毒证明了经典LAIV和嵌合H3 N2 + 4 M2 e LAIV之间的存活率的提高。总体而言，我们的研究结果表明，除了LAIV诱导的细胞免疫外，重组LAIV+4 M2 e诱导的M2 e特异性抗体在提供针对异源病毒的保护方面发挥重要作用。
Influenza viruses constantly evolve, reducing the overall protective effect of routine vaccination campaigns. Many different strategies are being explored to design universal influenza vaccines capable of protecting against evolutionary diverged viruses. The ectodomain of influenza A M2e protein (M2e) is among the most promising targets for universal vaccine design. Here, we generated two recombinant live attenuated influenza vaccines (LAIVs) expressing additional four M2e tandem repeats (4M2e) from the N-terminus of the viral hemagglutinin (HA) protein, in an attempt to enhance the M2e-mediated cross-protection. The recombinant H1N1+4M2e and H3N2+4M2e viruses retained growth characteristics attributable to traditional LAIV viruses and induced robust influenza-specific antibody responses in BALB/c mice, although M2e-specific antibodies were raised only after two-dose vaccination with LAIV+4M2e viruses. Mice immunized with either LAIV or LAIV+4M2e viruses were fully protected against a panel of heterologous influenza challenge viruses suggesting that antibody and cell-mediated immunity contributed to the protection. The protective role of the M2e-specific antibody was seen in passive serum transfer experiments, where enhancement in the survival rates between classical LAIV and chimeric H3N2+4M2e LAIV was demonstrated for H3N2 and H5N1 heterologous challenge viruses. Overall, the results of our study suggest that M2e-specific antibodies induced by recombinant LAIV+4M2e in addition to cellular immunity by LAIV play an important role in conferring protection against heterologous viruses.
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