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

Abstract

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.

• Authors: Chenguang Shen, Junyu Chen, Rui Li, Mengya Zhang, Guosong Wang, Svetlana Stegalkina, Limin Zhang, Jing Chen, Jianli Cao, Xingjian Bi, Stephen F Anderson, Timothy Alefantis, Minwei Zhang, Xiaoyang Cai, Kunyu Yang, Qingbing Zheng, Mujing Fang, Hai Yu, Wenxin Luo, Zizheng Zheng, Quan Yuan, Jun Zhang, James Wai-Kuo Shih, Harry Kleanthous, Honglin Chen, Yixin Chen, Ningshao Xia
• Journal: Science translational medicine (Sci Transl Med) Vol. 9 Issue 412 (Oct 18 2017) ISSN: 1946-6242 [Electronic] United States
• PMID: 29046433 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Antibodies, Neutralizing
• Antibodies, Viral
• Epitopes
• Hemagglutinin Glycoproteins, Influenza Virus
• Receptors, Virus
• Oseltamivir

Topics

• Animals
• Antibodies, Neutralizing (immunology, therapeutic use)
• Antibodies, Viral (immunology)
• Binding Sites
• Cross Protection (immunology)
• Dogs
• Drug Therapy, Combination
• Epitope Mapping
• Epitopes (immunology)
• Female
• Ferrets
• Hemagglutinin Glycoproteins, Influenza Virus (chemistry, metabolism)
• Immunization
• Influenza B virus (immunology, isolation & purification)
• Madin Darby Canine Kidney Cells
• Mice, Inbred BALB C
• Models, Molecular
• Orthomyxoviridae Infections (drug therapy, immunology, prevention & control, virology)
• Oseltamivir (therapeutic use)
• Protein Domains
• Receptors, Virus (metabolism)
• Treatment Outcome