Zhai Linlin, Zhang Limin, Jiang Yushan, Li Baisheng, Yang Minghui, Victorovich Khrustalev Vladislav, Aleksandrovna Khrustaleva Tatyana, Li Mengjun, Wang Yuelin, Huang Dong, Zeng Zhujun, Ren Zuning, Cao Hua, Zhu Li, Wu Qinghua, Xiao Weiwei, Zhang Bao, Wan Chengsong, Wang Fuxiang, Xia Ningshao, Zhao Wei, Chen Yixin, Shen Chenguang
BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, China.
J Med Virol. 2023 Jan;95(1):e28106. doi: 10.1002/jmv.28106. Epub 2022 Sep 6.
The discovery of broadly neutralizing monoclonal antibodies against influenza viruses has raised hope for the successful development of new antiviral drugs. However, due to the speed and variety of mutations in influenza viruses, single-component antibodies that recognize specific epitopes are susceptible to viral escape and have limited efficacy when administration is delayed. Hence, it is necessary to develop alternative strategies with better antiviral activity. Influenza B virus infection can cause severe illness in children and the elderly. Commonly used anti-influenza drugs have low clinical efficacy against influenza B virus. In this study, we investigated the antiviral efficacy of combinations of representative monoclonal antibodies targeting different antigenic epitopes against the influenza B virus. We found that combinations of antibodies recognizing the hemagglutinin (HA) head and stem regions showed a stronger neutralizing activity than single antibodies and other antibody combinations in vitro. In addition, we found that pair-wise combinations of antibodies recognizing the HA head region, HA stem region, and neuraminidase enzyme-activated region showed superior antiviral activity than single antibodies in both mouse and ferret in vivo protection assays. Notably, these antibody combinations still displayed good antiviral efficacy when treatment was delayed. Mechanistic studies further revealed that combining antibodies recognizing different epitope regions resulted in extremely strong antibody-dependent cell-mediated cytotoxicity, which may partly explain their superior antiviral effects. Together, the findings of this study provide new avenues for the development of better antiviral drugs and vaccines against influenza viruses.
针对流感病毒的广泛中和单克隆抗体的发现，为新型抗病毒药物的成功研发带来了希望。然而，由于流感病毒突变的速度和种类，识别特定表位的单组分抗体易受病毒逃逸影响，且给药延迟时疗效有限。因此，有必要开发具有更好抗病毒活性的替代策略。乙型流感病毒感染可导致儿童和老年人患重病。常用的抗流感药物对乙型流感病毒的临床疗效较低。在本研究中，我们研究了针对不同抗原表位的代表性单克隆抗体组合对乙型流感病毒的抗病毒疗效。我们发现，识别血凝素（HA）头部和茎部区域的抗体组合在体外显示出比单克隆抗体和其他抗体组合更强的中和活性。此外，我们发现，在小鼠和雪貂体内保护试验中，识别HA头部区域、HA茎部区域和神经氨酸酶酶激活区域的抗体两两组合显示出比单克隆抗体更优异的抗病毒活性。值得注意的是，这些抗体组合在治疗延迟时仍显示出良好的抗病毒疗效。机制研究进一步表明，识别不同表位区域的抗体组合会产生极强的抗体依赖性细胞介导的细胞毒性，这可能部分解释了它们优异的抗病毒效果。总之，本研究结果为开发更好的抗流感病毒药物和疫苗提供了新途径。
