A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve

Ying Fu, Zhen Zhang, Jared Sheehan, Yuval Avnir, Callie Ridenour, Thomas Sachnik, Jiusong Sun, M. Jaber Hossain, Li-Mei Chen, Quan Zhu, Ruben O. Donis and Wayne A. Marasco ()
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Ying Fu: Dana-Farber Cancer Institute, Harvard Medical School
Zhen Zhang: Dana-Farber Cancer Institute, Harvard Medical School
Jared Sheehan: Dana-Farber Cancer Institute, Harvard Medical School
Yuval Avnir: Dana-Farber Cancer Institute, Harvard Medical School
Callie Ridenour: Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases
Thomas Sachnik: Dana-Farber Cancer Institute, Harvard Medical School
Jiusong Sun: Dana-Farber Cancer Institute, Harvard Medical School
M. Jaber Hossain: Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases
Li-Mei Chen: Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases
Quan Zhu: Dana-Farber Cancer Institute, Harvard Medical School
Ruben O. Donis: Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases
Wayne A. Marasco: Dana-Farber Cancer Institute, Harvard Medical School

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Understanding the natural evolution and structural changes involved in broadly neutralizing antibody (bnAb) development holds great promise for improving the design of prophylactic influenza vaccines. Here we report an haemagglutinin (HA) stem-directed bnAb, 3I14, isolated from human memory B cells, that utilizes a heavy chain encoded by the IGHV3-30 germline gene. MAb 3I14 binds and neutralizes groups 1 and 2 influenza A viruses and protects mice from lethal challenge. Analysis of VH and VL germline back-mutants reveals binding to H3 and H1 but not H5, which supports the critical role of somatic hypermutation in broadening the bnAb response. Moreover, a single VLD94N mutation improves the affinity of 3I14 to H5 by nearly 10-fold. These data provide evidence that memory B cell evolution can expand the HA subtype specificity. Our results further suggest that establishing an optimized memory B cell pool should be an aim of ‘universal’ influenza vaccine strategies.

Date: 2016
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DOI: 10.1038/ncomms12780

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