A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve.
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.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachussetts 02215, USA.
Ying
0000-0002-3805-1028
Y
Fu
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachussetts 02215, USA.
Zhen
Z
Zhang
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachussetts 02215, USA.
Jared
J
Sheehan
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachussetts 02215, USA.
Yuval
Y
Avnir
Influenza Division, Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases, 1600 Clifton Road-Mail Stop G-16, Atlanta, Georgia 30333, USA.
Callie
C
Ridenour
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachussetts 02215, USA.
Thomas
T
Sachnik
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachussetts 02215, USA.
Jiusong
J
Sun
Influenza Division, Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases, 1600 Clifton Road-Mail Stop G-16, Atlanta, Georgia 30333, USA.
M Jaber
MJ
Hossain
Influenza Division, Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases, 1600 Clifton Road-Mail Stop G-16, Atlanta, Georgia 30333, USA.
Li-Mei
LM
Chen
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachussetts 02215, USA.
Quan
Q
Zhu
Influenza Division, Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases, 1600 Clifton Road-Mail Stop G-16, Atlanta, Georgia 30333, USA.
Ruben O
RO
Donis
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachussetts 02215, USA.
Wayne A
WA
Marasco
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D000915:Antibody Affinity; D001402:B-Lymphocytes / Q000502:physiology*; D005075:Biological Evolution; D018604:Epitope Mapping; D000939:Epitopes; D015967:Gene Expression Regulation, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics*; D009980:Influenza A virus / Q000235:genetics; D007252:Influenza Vaccines / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology / Q000821:virology*; D051379:Mice; D008958:Models, Molecular; D009976:Orthomyxoviridae Infections / Q000517:prevention & control / Q000662:veterinary; D010802:Phylogeny; D011485:Protein Binding; D011487:Protein Conformation
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines