Broadly neutralizing antibodies target a haemagglutinin anchor epitope

Abstract

Broadly neutralizing antibodies that target epitopes of haemagglutinin on the influenza virus have the potential to provide near universal protection against influenza virus infection1. However, viral mutants that escape broadly neutralizing antibodies have been reported2,3. The identification of broadly neutralizing antibody classes that can neutralize viral escape mutants is critical for universal influenza virus vaccine design. Here we report a distinct class of broadly neutralizing antibodies that target a discrete membrane-proximal anchor epitope of the haemagglutinin stalk domain. Anchor epitope-targeting antibodies are broadly neutralizing across H1 viruses and can cross-react with H2 and H5 viruses that are a pandemic threat. Antibodies that target this anchor epitope utilize a highly restricted repertoire, which encodes 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 repertoire and were recalled in humans by an oil-in-water adjuvanted chimeric haemagglutinin vaccine4,5, which is 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 broadly neutralizing antibodies that are widespread in the human memory B cell pool.

Functional antibodies exhibit light chain coherence

“…consistent VDJ gene identification) and enough donor information to distinguish bona fide recurrence from clonal expansion within given individuals. Generation of such truth data at scale is feasible using existing methods 21,[38][39][40][41] .…”

“…A clonotype can therefore be treated as the minimal functional group of antibodies. Next, as has been observed, nature repeats itself by creating similar clonotypes that appear to have the same function 2-21 , and these might be combined into groups. Such recurrences have been observed between donors, but also occur within single donors, as we will demonstrate.…”

“…Each chain contains three complementarity-determining regions (CDR1-3), contributing to antigen specificity. Certain heavy and light chains are preferred for particular antigens 2–21 . We considered pairs of B cells sharing the same heavy chain V gene and CDRH3 amino acid sequence and isolated from different donors, also known as public clonotypes 22,23 .…”

“…Specific examples suggest that sequence similarity can guide the way to understanding functional groups. For example, in the case of influenza virus, antibodies binding the anchor epitope of the haemagglutinin stalk domain reuse four heavy chain V genes and two light chain V genes 21 . A similar observation has been made in the case of Zika virus, where a protective heavy-light pair IGVH3-23 / IGVK1-5 is observed in multiple humans, which also cross-reacts with dengue virus 16 .…”

Induction of broadly reactive influenza antibodies increases susceptibility to autoimmunity

“…Many factors contribute to the paucity of broadly neutralizing influenza antibodies, including steric hindrance and molecular constraints caused by the proximity of some conserved epitopes to the viral membrane (Angeletti and Yewdell, 2018b;Guthmiller et al, 2021;Krammer, 2016;Lee and Wilson, 2015). A prevailing hypothesis was that B cells with high-affinity receptors specific for the variable epitopes outcompete B cells specific for conserved HA epitopes in germinal centers (Angeletti and Yewdell, 2018a).…”