A Broadly Neutralizing Human Monoclonal Antibody Directed against a Novel Conserved Epitope on the Influenza Virus H3 Hemagglutinin Globular Head

Abstract

Most neutralizing antibodies elicited during influenza virus infection or vaccination target immunodominant, variable epitopeson the globular head region of hemagglutinin (HA), which leads to narrow strain protection. In this report, we describe the properties of a unique anti-HA monoclonal antibody (MAb), D1-8, that was derived from human B cells and exhibits potent, broad neutralizing activity across antigenically diverse influenza H3 subtype viruses. Based on selection of escape variants, we show that D1-8 targets a novel epitope on the globular head region of the influenza virus HA protein. The HA residues implicated in D1-8 binding are highly conserved among H3N2 viruses and are located proximal to antigenic site D. We demonstrate that the potent in vitro antiviral activity of D1-8 translates into protective activity in mouse models of influenza virus infection. Furthermore, D1-8 exhibits superior therapeutic survival benefit in influenza virus-infected mice compared to the neuraminidase inhibitor oseltamivir when treatment is started late in infection. The present study suggests the potential application of this monoclonal antibody for the therapeutic treatment of H3N2 influenza virus infection. IMPORTANCERecently, a few globular head-targeting MAbs have been discovered that exhibit activity against different subtypes of influenza subtypes, such as H1; however, none of the previously described MAbs showed broadly neutralizing activity against diverse H3 viruses. In this report, we describe a human MAb, D1-8, that exhibits potent, broadly neutralizing activity against antigenically diverse H3 subtype viruses. The genotypic analysis of escape mutants revealed a unique putative epitope region in the globular head of H3 HA that is comprised of highly conserved residues and is distinct from the receptor binding site. Furthermore, we demonstrate that D1-8 exhibits superior therapeutic efficacy in influenza virus-infected mice compared to the neuraminidase inhibitor oseltamivir when treatment is started late in infection. In addition to describing a novel anti-globular head of H3 HA MAb with potent broadly neutralizing activity, our report suggests the potential of D1-8 for therapeutic treatment of seasonal influenza virus H3 infection.

Antibody Responses to Trivalent Inactivated Influenza Vaccine in Health Care Personnel Previously Vaccinated and Vaccinated for The First Time

“…Cross-reactive HA-specific antibodies might target the conserved region near the receptor-binding site of hemagglutinin head, although the majority of HA cross-reactive antibodies would recognize the stem region26272829. Other conserved neutralizing epitopes on the H3 HA head have also been described3031. Nevertheless, it is unclear about the protective level of these cross-reactive HA-specific antibodies and the declining trend of the HI titer with the time within previously vaccinated individuals.…”

A human monoclonal antibody derived from a vaccinated volunteer recognizes heterosubtypically a novel epitope on the hemagglutinin globular head of H1 and H9 influenza A viruses

“…An H5N1-specific mouse MAb HA-7 was shown to recognize a structural epitope that consists of two segments, NV/PE at residues 87-79 and HFEKIW at residues 113-118; the latter overlaps the epitope identified in this study [27]. A HuMAb D1-8, which is derived from human antibody VH and VL repertoires and specific to H3 influenza viruses, was reported to target a conserved epitope between antigenic sites D and E at the globular head of H3 HA [25], which correspond to Ca1 and Cb, respectively, in H1 HA.…”

“…Most heterosubtypic crossneutralizing HuMAb have been reported to recognize epitopes located mainly in the most conserved HA stem region [7,10,14,23]. Also, a few HuMAbs that target relatively conserved epitopes adjacent to or overlapping the RBS in the head region were shown to be subtype-specific [17,25,26]. To our knowledge, 5D7 is the first heterosubtypic neutralizing HuMAb that targets a conserved epitope distinct from the RBS in the HA globular head region.…”

Broadly neutralizing antibodies for therapy of viral infections

“…76 Benjamin et al 77 described the discovery of a unique anti-HA mAb, D1-8, that was derived from human B-cells and exhibits potent, broad neutralizing activity across antigenically diverse influenza H3 subtype viruses. D1-8 targets a novel epitope on the globular head region of the influenza virus HA protein.…”

“…D1-8 targets a novel epitope on the globular head region of the influenza virus HA protein. 77 More recently, Skountzou et al 78 have demonstrated in mice that IgM antibodies are functionally similar to IgG, as they neutralized the influenza virus in the presence of complement.…”