A universal monoclonal antibody protects against all influenza A and B viruses by targeting a highly conserved epitope in the viral neuraminidase

Abstract

BackgroundHemagglutinin (HA) and neuraminidase (NA) are thetwo major surface glycoproteins of influenza viruses andthe main targets of vaccine-induced antibodies (Abs).While several broadly neutralizing Abs targeting con-served epitopes in diverse HA subtypes have been iso-lated, NA-specific Abs could only cross-protect partiallyagainst homologous and heterologous strains from thesame subtype.Materials and methodsComprehensive bioinformatics analyses of all publiclyavailable full-length NA sequences using multiple align-ments and Shannon entropy were conducted to identifyconserved sequences in all influenza A and B viral NA [1].Growth kinetics of wild-type or recombinant viruses withsingle alanine substitutions within the identified regionswas then analyzed in MDCK cells. A rabbit monoclonalAb (mAb), denoted as HCA-2, raised against one of thecharacterized sequences was then examined for its in vitroinhibitory effects and in vivo prophylactic efficacy againstseveral influenza A and B strains.ResultsBioinformatics analyses uncovered a universally con-served 9-mer peptide amongst all influenza NA proteins(amino acids 222-230 and comprised of “ILRTQESEC”).Substitutions within this universal epitope underscoredits crucial roles in viral fitness and replication [2].Importantly, the HCA-2 mAb showed broad in vitroinhibition against multiple strains from all influenza ANA subtypes (N1-N9) and influenza B viruses from bothVictoria and Yamagata genetic lineages [3,4]. It also pro-vided heterosubtypic protection in mice against lethaldoses of H1N1 and H3N2 strains. Finally, amino acidresidues I222 and E227, located in close proximity tothe active site, were found to be indispensable for inhi-bition by this mAb [3,4].ConclusionsThese findings reveal the essential role of this uniquehighly-conserved sequence in NA function and viralreplication and indicate that it is sufficiently exposed toallow access by inhibitory antibody during the course ofinfection. Thus, it could represent a potential target fornovel antivirals or targeted-vaccines against diversestrains of influenza A and B viruses.