Broadly neutralizing antibodies (bnAbs) targeting epitopes of the influenza virus hemagglutinin (HA) have the potential to provide near universal protection against influenza virus infection. However, viral mutants that escape bnAbs have been reported. The identification of bnAb classes that can neutralize viral escape mutants is critical for universal influenza virus vaccine design. Here, we report a distinct class of bnAbs targeting a discrete membrane-proximal anchor epitope of the HA stalk domain. Anchor epitope-targeting antibodies are broadly neutralizing across H1 viruses and can cross-react with pandemic-threat H2 and H5 viruses. Antibodies targeting this anchor epitope utilize a highly restricted repertoire, which encodes for two public binding motifs that make extensive contacts with conserved residues in the fusion peptide. Moreover, anchor epitope-targeting B cells are common in the human memory B cell (MBC) repertoire and were recalled in humans by an oil-in-water adjuvanted chimeric HA (cHA) vaccine, a potential universal influenza virus vaccine. To maximize protection against seasonal and pandemic influenza viruses, vaccines should aim to boost this previously untapped source of bnAbs that are widespread in the human MBC pool.
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.