Rapid development of broadly influenza neutralizing antibodies through redundant mutations

Leontios Pappas, Mathilde Foglierini, Luca Piccoli, Nicole L. Kallewaard, Filippo Turrini, Chiara Silacci, Blanca Fernandez-Rodriguez, Gloria Agatic, Isabella Giacchetto-Sasselli, Gabriele Pellicciotta, Federica Sallusto, Qing Zhu, Elisa Vicenzi, Davide Corti, Antonio Lanzavecchia

Research output: Contribution to journalArticlepeer-review

Abstract

The neutralizing antibody response to influenza virus is dominated by antibodies that bindto the globular head of haemagglutinin,which undergoes acontinuous antigenic drift, necessitating the re-formulation of influenza vaccines onan annual basis. Recently, several laboratories have described a new class of rare influenza-neutralizing antibodies that target a conserved site in the haemagglutinin stem1-6. Most of these antibodies use the heavy-chain variable region VH1-69 gene, and structural data demonstrate that they bind to the haemagglutinin stem through conserved heavy-chain complementarity determining region(HCDR)residues.However, the VH1-69 antibodies are highly mutated and are produced by some but not all individuals6,7, suggesting that several somatic mutations may be required for their development8,9. To address this, here we characterize 197 anti-stem antibodies froma single donor, reconstruct the developmental pathways of severalVH1-69 clones and identify two key elements that are required for the initial development of most VH1-69 antibodies: a polymorphic germline-encoded phenylalanine at position 54 and a conserved tyrosine at position 98 inHCDR3. Strikingly, in most cases a single proline to alanine mutation at position 52a in HCDR2 is sufficient to confer high affinity binding to the selecting H1 antigen, consistent with rapid affinity maturation. Surprisingly, additional favourable mutations continue to accumulate, increasing the breadth of reactivity andmaking both the initialmutations and phenylalanine at position 54 functionally redundant. These results defineVH1-69 allele polymorphism, rearrangement of the VDJ gene segments and single somatic mutations as the three requirements for generating broadly neutralizing VH1-69 antibodies and reveal an unexpected redundancy in the affinity maturation process.

Original languageEnglish
Pages (from-to)418-422
Number of pages5
JournalNature
Volume516
Issue number7531
DOIs
Publication statusPublished - Dec 18 2014

ASJC Scopus subject areas

  • General
  • Medicine(all)

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