A public broadly neutralizing antibody class targets a membrane-proximal anchor epitope of influenza virus hemagglutinin

Abstract

Broadly neutralizing antibodies against influenza virus hemagglutinin (HA) have the potential to provide universal protection against influenza virus infections. Here, we report a distinct class of broadly neutralizing antibodies targeting an epitope toward the bottom of the HA stalk domain where HA is anchored to the viral membrane. Antibodies targeting this membrane-proximal anchor epitope utilized a highly restricted repertoire, which encode for two conserved motifs responsible for HA binding. Anchor targeting B cells were common in the human memory B cell repertoire across subjects, indicating pre-existing immunity against this epitope. Antibodies against the anchor epitope at both the serological and monoclonal antibody levels were potently induced in humans by a chimeric HA vaccine, a potential universal influenza virus vaccine. Altogether, this study reveals an under appreciated class of broadly neutralizing antibodies against H1-expressing viruses that can be robustly recalled by a candidate universal influenza virus vaccine.

B Cell Responses against Influenza Viruses: Short-Lived Humoral Immunity against a Life-Long Threat

“…Notably, one antibody binding the broadly neutralizing stalk epitope, CR9114, can neutralize group 1 and 2 IAVs as well as provide protection against influenza B viruses [ 39 ]. A second class of bnAbs targeting a membrane-proximal anchor epitope of the H1 stalk ( Figure 1 B) were recently identified and are broadly neutralizing across H1-expressing viruses [ 45 , 46 ]. Lastly, a third class of bnAbs targeting the stalk domain of group 2 viruses ( Figure 1 C) have been characterized and have a distinct binding footprint relative to antibodies targeting the broadly neutralizing stalk epitope [ 47 , 48 ].…”

“…B cells against the HA stalk may be disadvantaged in terms of their ability to reach these epitopes because the HA stalk domain sits within the viral membrane and virions are highly decorated with glycoproteins, limiting access to these epitopes [ 158 , 159 ]. Notably, HA stalk-binding antibodies have reduced affinity for the full virus relative to recombinant HA, as the viral membrane and nearby glycoproteins reduce accessibility [ 2 , 46 ]. Moreover, the RBS on the HA head is an exceptionally small epitope, with most antibodies using only heavy chain complementarity-determining region 3 (CDR3) to bind the conserved residues of the RBS [ 12 , 14 ].…”

“…VH1-69-expressing B cells often express a patch of hydrophobic residues within the H-CDR2 loop that are critical for antigen binding. Additional classes of stalk-binding antibodies and antibodies targeting the lateral patch of the HA head similarly utilize restricted repertoire features that are critical for epitope binding [ 20 , 42 , 43 , 46 ]. Moreover, RBS-binding antibodies typically possess long H-CDR3s, which mimics sialic acid binding [ 12 , 14 , 15 ].…”

“…As people have little to no pre-existing immunity against the variable epitopes of avian IAV subtypes, people would preferentially recall MBCs against conserved epitopes on the HA stalk. Notably, a phase I clinical trial of an H1 cHA vaccine trial showed humans could recall MBCs against multiple conserved epitopes of the HA stalk domain and the trimer interface epitope of the HA head [ 46 , 157 , 181 ].…”

“…Influenza virus vaccines that use oil-in-water adjuvants are noted for their ability to activate and promote the affinity maturation of both naïve B cells and MBCs [ 192 , 193 ]. Furthermore, a phase I clinical trial of the group 1 cHA vaccine revealed that only subjects that received the inactivated vaccine with the adjuvant AS03 substantially seroconverted against the HA stalk domain [ 46 , 157 , 181 ]. Taken together, these studies indicate the critical role of adjuvants in promoting antibody responses against conserved epitopes of HA.…”