Abstract
Effective annual influenza vaccination requires frequent changes in vaccine composition due to both antigenic shift for different subtype hemagglutinins (HAs) and antigenic drift in a particular HA. Here we present a broadly neutralizing human monoclonal antibody with an unusual binding modality. The antibody, designated CT149, was isolated from convalescent patients infected with pandemic H1N1 in 2009. CT149 is found to neutralize all tested group 2 and some group 1 influenza A viruses by inhibiting low pH-induced, HA-mediated membrane fusion. It promotes killing of infected cells by Fc-mediated antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. X-ray crystallographic data reveal that CT149 binds primarily to the fusion domain in HA2, and the light chain is also largely involved in binding. The epitope recognized by this antibody comprises amino-acid residues from two adjacent protomers of HA. This binding characteristic of CT149 will provide more information to support the design of more potent influenza vaccines.
Highlights
Effective annual influenza vaccination requires frequent changes in vaccine composition due to both antigenic shift for different subtype hemagglutinins (HAs) and antigenic drift in a particular HA
We present the isolation of a broadly neutralizing antibody, CT149, from convalescent patients infected with A(H1N1)pdm[09]
We reveal that CT149 exhibits potent neutralization in cell-based tests for divergent HA subtypes and good protection from H1N1, H3N2 and H5N1 subtype viruses and, especially, from the recently emerged human-infecting H7N9 virus[21,22,23] in the mouse model
Summary
Effective annual influenza vaccination requires frequent changes in vaccine composition due to both antigenic shift for different subtype hemagglutinins (HAs) and antigenic drift in a particular HA. MAbs produced by immortalized cells in industrial bioreactors would offer an unlimited supply of homogeneous antibody for therapeutic or prophylactic use, yet the highly variable nature of most neutralization epitopes on the influenza hemagglutinin (HA) molecule proposes a problem. Recent reports indicate that human mAbs targeting a conserved region on the stem of the HA spikes are protective in mouse models of infection[15,16,17,18,19,20] These mAbs could be derived from VH and VL (variable region sequences of the heavy-chain (VH) and light-chain (VL)) loci complementary DNA (cDNA) phage display libraries prepared from human immunoglobulin M (IgM)-positive memory cells of influenza-vaccinated or non-vaccinated donors[15,16,17]. We show that the epitope recognized by CT149 is present in the stem region spanning across two adjacent protomers
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