Kotomina Tatiana, Isakova-Sivak Irina, Kim Ki-Hye, Park Bo Ryoung, Jung Yu-Jin, Lee Youri, Mezhenskaya Daria, Matyushenko Victoria, Kang Sang-Moo, Rudenko Larisa
Department of Virology, Institute of Experimental Medicine, Saint Petersburg 197376, Russia.
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
Vaccines (Basel). 2020 Nov 3;8(4):648. doi: 10.3390/vaccines8040648.
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.
流感病毒不断进化,降低了常规疫苗接种活动的总体保护效果。目前正在探索许多不同的策略来设计能够抵御进化分歧病毒的通用流感疫苗。甲型流感病毒M2e蛋白(M2e)的胞外域是通用疫苗设计中最有前景的靶点之一。在此,我们构建了两种重组减毒活流感疫苗(LAIV),它们从病毒血凝素(HA)蛋白的N端额外表达四个M2e串联重复序列(4M2e),以增强M2e介导的交叉保护作用。重组H1N1 + 4M2e和H3N2 + 4M2e病毒保留了传统LAIV病毒的生长特性,并在BALB/c小鼠中诱导了强烈的流感特异性抗体反应,不过只有在用LAIV + 4M2e病毒进行两剂疫苗接种后才产生M2e特异性抗体。用LAIV或LAIV + 4M2e病毒免疫的小鼠对一组异源流感攻击病毒具有完全的保护作用,这表明抗体和细胞介导的免疫都有助于提供保护。在被动血清转移实验中观察到了M2e特异性抗体的保护作用,其中对于H3N2和H5N1异源攻击病毒,经典LAIV和嵌合H3N2 + 4M2e LAIV之间的存活率有所提高。总体而言,我们的研究结果表明,重组LAIV + 4M2e诱导的M2e特异性抗体以及LAIV诱导的细胞免疫在提供针对异源病毒的保护中发挥了重要作用。
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