3 years ago

A multimechanistic antibody targeting the receptor binding site potently cross-protects against influenza B viruses.

Qingbing Zheng, Xingjian Bi, Guosong Wang, Zizheng Zheng, Hai Yu, Stephen F Anderson, Yixin Chen, Xiaoyang Cai, Minwei Zhang, Kunyu Yang, Svetlana Stegalkina, James Wai-Kuo Shih, Quan Yuan, Chenguang Shen, Wenxin Luo, Rui Li, Ningshao Xia, Timothy Alefantis, Honglin Chen, Limin Zhang, Mengya Zhang, Mujing Fang, Junyu Chen, Jun Zhang, Jing Chen, Harry Kleanthous, Jianli Cao
Influenza B virus causes considerable disease burden worldwide annually, highlighting the limitations of current influenza vaccines and antiviral drugs. In recent years, broadly neutralizing antibodies (bnAbs) against hemagglutinin (HA) have emerged as a new approach for combating influenza. We describe the generation and characterization of a chimeric monoclonal antibody, C12G6, that cross-neutralizes representative viruses spanning the 76 years of influenza B antigenic evolution since 1940, including viruses belonging to the Yamagata, Victoria, and earlier lineages. Notably, C12G6 exhibits broad cross-lineage hemagglutination inhibition activity against influenza B viruses and has higher potency and breadth of neutralization when compared to four previously reported influenza B bnAbs. In vivo, C12G6 confers stronger cross-protection against Yamagata and Victoria lineages of influenza B viruses in mice and ferrets than other bnAbs or the anti-influenza drug oseltamivir and has an additive antiviral effect when administered in combination with oseltamivir. Epitope mapping indicated that C12G6 targets a conserved epitope that overlaps with the receptor binding site in the HA region of influenza B virus, indicating why it neutralizes virus so potently. Mechanistic analyses revealed that C12G6 inhibits influenza B viruses via multiple mechanisms, including preventing viral entry, egress, and HA-mediated membrane fusion and triggering antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity responses. C12G6 is therefore a promising candidate for the development of prophylactics or therapeutics against influenza B infection and may inform the design of a truly universal influenza vaccine.

Publisher URL: http://doi.org/10.1126/scitranslmed.aam5752

DOI: 10.1126/scitranslmed.aam5752

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