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      Structural and genetic basis for development of broadly neutralizing influenza antibodies

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          Abstract

          The events leading to the generation of broadly neutralizing antibodies to influenza viruses, which may hold the key to developing a universal flu vaccine, are elucidated.

          Supplementary information

          The online version of this article (doi:10.1038/nature11371) contains supplementary material, which is available to authorized users.

          Vaccine-friendly anti-influenza antibodies

          The study of broadly neutralizing antibodies to influenza virus may pave the way for the generation of a universal vaccine. Here, Daniel Lingwood et al. define the minimal requirements for high-affinity binding of such broadly neutralizing antibodies. They show that binding does not involve light chains, and that most of the crucial heavy-chain contacts are germline encoded. Membrane-bound antibodies are shown to function despite their initially very low affinity.

          Supplementary information

          The online version of this article (doi:10.1038/nature11371) contains supplementary material, which is available to authorized users.

          Abstract

          Influenza viruses take a yearly toll on human life despite efforts to contain them with seasonal vaccines. These viruses evade human immunity through the evolution of variants that resist neutralization. The identification of antibodies that recognize invariant structures on the influenza haemagglutinin (HA) protein have invigorated efforts to develop universal influenza vaccines. Specifically, antibodies to the highly conserved stem region of HA neutralize diverse viral subtypes. These antibodies largely derive from a specific antibody gene, heavy-chain variable region IGHV1-69, after limited affinity maturation from their germline ancestors 1, 2 , but how HA stimulates naive B cells to mature and induce protective immunity is unknown. To address this question, we analysed the structural and genetic basis for their engagement and maturation into broadly neutralizing antibodies. Here we show that the germline-encoded precursors of these antibodies act as functional B-cell antigen receptors (BCRs) that initiate subsequent affinity maturation. Neither the germline precursor of a prototypic antibody, CR6261 (ref. 3), nor those of two other natural human IGHV1-69 antibodies, bound HA as soluble immunoglobulin-G (IgG). However, all three IGHV1-69 precursors engaged HA when the antibody was expressed as cell surface IgM. HA triggered BCR-associated tyrosine kinase signalling by germline transmembrane IgM. Recognition and virus neutralization was dependent solely on the heavy chain, and affinity maturation of CR6261 required only seven amino acids in the complementarity-determining region (CDR) H1 and framework region 3 (FR3) to restore full activity. These findings provide insight into the initial events that lead to the generation of broadly neutralizing antibodies to influenza, informing the rational design of vaccines to elicit such antibodies and providing a model relevant to other infectious diseases, including human immunodeficiency virus/AIDS. The data further suggest that selected immunoglobulin genes recognize specific protein structural ‘patterns’ that provide a substrate for further affinity maturation.

          Supplementary information

          The online version of this article (doi:10.1038/nature11371) contains supplementary material, which is available to authorized users.

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          Most cited references21

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          Standard conformations for the canonical structures of immunoglobulins.

          A comparative analysis of the main-chain conformation of the L1, L2, L3, H1 and H2 hypervariable regions in 17 immunoglobulin structures that have been accurately determined at high resolution is described. This involves 79 hypervariable regions in all. We also analysed a part of the H3 region in 12 of the 15 VH domains considered here. On the basis of the residues at key sites the 79 hypervariable regions can be assigned to one of 18 different canonical structures. We show that 71 of these hypervariable regions have a conformation that is very close to what can be defined as a "standard" conformation of each canonical structure. These standard conformations are described in detail. The other eight hypervariable regions have small deviations from the standard conformations that, in six cases, involve only the rotation of a single peptide group. Most H3 hypervariable regions have the same conformation in the part that is close to the framework and the details of this conformation are also described here. Copyright 1997 Academic Press Limited
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            Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine.

            The target of neutralizing antibodies that protect against influenza virus infection is the viral protein HA. Genetic and antigenic variation in HA has been used to classify influenza viruses into subtypes (H1-H16). The neutralizing antibody response to influenza virus is thought to be specific for a few antigenically related isolates within a given subtype. However, while heterosubtypic antibodies capable of neutralizing multiple influenza virus subtypes have been recently isolated from phage display libraries, it is not known whether such antibodies are produced in the course of an immune response to influenza virus infection or vaccine. Here we report that, following vaccination with seasonal influenza vaccine containing H1 and H3 influenza virus subtypes, some individuals produce antibodies that cross-react with H5 HA. By immortalizing IgG-expressing B cells from 4 individuals, we isolated 20 heterosubtypic mAbs that bound and neutralized viruses belonging to several HA subtypes (H1, H2, H5, H6, and H9), including the pandemic A/California/07/09 H1N1 isolate. The mAbs used different VH genes and carried a high frequency of somatic mutations. With the exception of a mAb that bound to the HA globular head, all heterosubtypic mAbs bound to acid-sensitive epitopes in the HA stem region. Four mAbs were evaluated in vivo and protected mice from challenge with influenza viruses representative of different subtypes. These findings reveal that seasonal influenza vaccination can induce polyclonal heterosubtypic neutralizing antibodies that cross-react with the swine-origin pandemic H1N1 influenza virus and with the highly pathogenic H5N1 virus.
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              Induction of broadly neutralizing H1N1 influenza antibodies by vaccination.

              The rapid dissemination of the 2009 pandemic influenza virus underscores the need for universal influenza vaccines that elicit protective immunity to diverse viral strains. Here, we show that vaccination with plasmid DNA encoding H1N1 influenza hemagglutinin (HA) and boosting with seasonal vaccine or replication-defective adenovirus 5 vector encoding HA stimulated the production of broadly neutralizing influenza antibodies. This prime/boost combination increased the neutralization of diverse H1N1 strains dating from 1934 to 2007 as compared to either component alone and conferred protection against divergent H1N1 viruses in mice and ferrets. These antibodies were directed to the conserved stem region of HA and were also elicited in nonhuman primates. Cross-neutralization of H1N1 subtypes elicited by this approach provides a basis for the development of a universal influenza vaccine for humans.
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                Author and article information

                Contributors
                gnabel@nih.gov
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                29 August 2012
                2012
                : 489
                : 7417
                : 566-570
                Affiliations
                GRID grid.419681.3, ISNI 0000 0001 2164 9667, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, ; Bethesda, 20892-3005 Maryland USA
                Article
                BFnature11371
                10.1038/nature11371
                7095019
                22932267
                b8604e8d-787d-400f-bc8f-396df2622be7
                © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2012

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 5 May 2012
                : 29 June 2012
                Categories
                Article
                Custom metadata
                © Springer Nature Limited 2012

                Uncategorized
                immunogenetics,antibodies,influenza virus
                Uncategorized
                immunogenetics, antibodies, influenza virus

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