Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses

Grandea, Andres G.; Olsen, Ole; Cox, Thomas C.; Renshaw, Mark W.; Hammond, Philip W.; Chan-Hui, Po-Ying; Mitcham, Jennifer L.; Cieplak, Witold; Stewart, Shaun; Grantham, Michael L.; Pekosz, Andrew; Kiso, Maki; Shinya, Kyoko; Hatta, Masato; Kawaoka, Yoshihiro; Moyle, Matthew

doi:10.1073/pnas.0911806107

Cited by 120 publications

(113 citation statements)

References 39 publications

(34 reference statements)

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“…A study using mouse MAbs showed that, in addition to anti-HA antibodies, NA-and nucleoprotein-specific MAbs mediated CDL of influenza virus-infected target cells, but matrix protein 1-specific MAbs did not (25). Recently Grandea et al reported that human MAbs specific to an epitope on the highly conserved ectodomain of matrix protein 2 (M2) were able to mediate CDL of CHO cells stably expressing M2 (6). M2 is known to be expressed abundantly at the cell surface (10).…”

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confidence: 99%

Complement-Dependent Lysis of Influenza A Virus-Infected Cells by Broadly Cross-Reactive Human Monoclonal Antibodies

Terajima

Cruz

et al. 2011

J Virol

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We characterized human monoclonal antibodies (MAbs) cloned from influenza virus-infected patients and from influenza vaccine recipients by complement-dependent lysis (CDL) assay. Most MAbs active in CDL were neutralizing, but not all neutralizing MAbs can mediate CDL. Two of the three stalk-specific neutralizing MAbs tested were able to mediate CDL and were more cross-reactive to temporally distant H1N1 strains than the conventional hemagglutination-inhibiting and neutralizing MAbs. One of the stalk-specific MAbs was subtype cross-reactive to H1 and H2 hemagglutinins, suggesting a role for stalk-specific antibodies in protection against influenza illness, especially by a novel viral subtype which can cause pandemics.

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confidence: 99%

Complement-Dependent Lysis of Influenza A Virus-Infected Cells by Broadly Cross-Reactive Human Monoclonal Antibodies

Terajima

Cruz

et al. 2011

J Virol

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“…Protection induced by M2e-based vaccines such as M2e displayed on recombinant virus-like particles is mediated by antibodies (11) and, like the in vitro broadly neutralizing HA stalk-specific antibodies (16), depends on activating Fc␥ receptors (11,16,17). In line with this, passive transfer of mouse and human monoclonal antibodies directed against M2e can protect against influenza A virus challenge (11,(18)(19)(20)(21). It has also been reported that treatment of experimentally challenged human volunteers with a human monoclonal antibody directed against M2e reduces viral replication and clinical symptoms (22).…”

mentioning

confidence: 82%

Structure of the Extracellular Domain of Matrix Protein 2 of Influenza A Virus in Complex with a Protective Monoclonal Antibody

Cho

Schepens

Seok

et al. 2015

J Virol

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The extracellular domain of influenza A virus matrix protein 2 (M2e) is conserved and is being evaluated as a quasiuniversal influenza A vaccine candidate. We describe the crystal structure at 1.6 Å resolution of M2e in complex with the Fab fragment of an M2e-specific monoclonal antibody that protects against influenza A virus challenge. This antibody binds M2 expressed on the surfaces of cells infected with influenza A virus. Five out of six complementary determining regions interact with M2e, and three highly conserved M2e residues are critical for this interaction. In this complex, M2e adopts a compact U-shaped conformation stabilized in the center by the highly conserved tryptophan residue in M2e. This is the first description of the three-dimensional structure of M2e. IMPORTANCEM2e of influenza A is under investigation as a universal influenza A vaccine, but its three-dimensional structure is unknown. We describe the structure of M2e stabilized with an M2e-specific monoclonal antibody that recognizes natural M2. We found that the conserved tryptophan is positioned in the center of the U-shaped structure of M2e and stabilizes its conformation. The structure also explains why previously reported in vivo escape viruses, selected with a similar monoclonal antibody, carried proline residue substitutions at position 10 in M2. Matrix protein 2 (M2) is a structural protein of influenza A viruses and plays an important role in the virus life cycle. This type III membrane protein of 96 amino acid residues has an N-terminal ectodomain (M2e) of 23 residues, a transmembrane domain of 19 residues, and a cytoplasmic domain of 54 residues (1). M2 is classified as a viroporin. Mutational analysis and crystal and nuclear magnetic resonance (NMR) structural analysis of the M2 transmembrane domain revealed that it is composed of a fourstranded coiled coil and that two conserved amino acid residues (M2-His37 and -Trp41) have a key role in acid-induced proton gating (2-5). Following endocytosis of influenza A virions, the acidic endosomal environment activates the M2 channel so that protons enter the virion interior. The resulting acidification loosens the viral ribonucleoprotein complexes from matrix protein 1 (M1), which facilitates their migration through the membrane fusion pore into the host cell cytoplasm (6, 7). M2 can activate the inflammasome, impairs autophagosome maturation, and was recently shown to recruit parts of the autophagosome machinery to sites of virus budding by a conserved motif in its cytoplasmic domain (8, 9).The sequence of M2e is conserved and therefore has frequently been explored for the development of a universal influenza A vaccine (10-13). Immune protection by M2e-directed vaccines has been documented extensively in experimental animal models, including mice, ferrets, and swine (11-13). In addition, a phase I clinical study showed that M2e-based vaccines are safe and immunogenic in humans (10,14). Seasonal influenza A virus infection induces a poor immune responses to M2e, but this weak re...

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“…Similarly, Vella et al reported that adult subjects who received the A/Victoria/3/75(H3N2) inactivated influenza vaccine showed a significant rise in ADCC specific immune lysis (SIL) and developed ADCC antibody titers similar to naturally infected subjects (27). Grandea et al found that monoclonal antibodies derived from healthy subjects, which recognized a highly conserved epitope within the ectodomain of the influenza matrix 2 protein, protected mice from lethal challenge with H5N1 and A(H1N1)pdm09 influenza virus strains, with in vitro evidence suggesting that ADCC and/or CDL antibodies mediated this protection (6). A recent paper by Dilillo et al demonstrated that Fc-FccR interactions are required for stalk-specific, but not globular head-specific, monoclonal antibody-mediated protection during in vivo challenge in mice, suggesting a role for ADCC in protection against influenza via stalk-specific antibodies (2).…”

Section: Introductionmentioning

confidence: 99%

Relationship of Preexisting Influenza Hemagglutination Inhibition, Complement-Dependent Lytic, and Antibody-Dependent Cellular Cytotoxicity Antibodies to the Development of Clinical Illness in a Prospective Study of A(H1N1)pdm09 Influenza in Children

Terajima

Thomas

et al. 2014

Viral Immunology

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The hemagglutination inhibition (HAI) antibody titer is considered the primary immune correlate of protection for influenza. However, recent studies have highlighted the limitations on the use of the HAI titer as a correlate in at-risk populations such as children and older adults. In addition to the neutralization of cell-free virus by antibodies to hemagglutinin and interference of virus release from infected cells by antibodies to neuraminidase, influenza virus-specific antibodies specifically can bind to infected cells and lyse virus-infected cells through the activation of complement or natural killer (NK) cells, via antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent lysis (CDL). We evaluated preexisting HAI, CDL, and ADCC antibodies in young children enrolled in a prospective cohort study of dengue during the epidemic with influenza A(H1N1)pdm09 virus to determine associations between preexisting antibodies and the occurrence of clinical or subclinical influenza virus infection. Though both preexisting HAI and CDL antibodies were associated with protection against clinical influenza, our data suggested that CDL was not a better correlate than HAI. We found that ADCC antibodies behaved differently from HAI and CDL antibodies. Unlike HAI and CDL antibodies, preexisting ADCC antibodies did not correlate with protection against clinical influenza. In fact, ADCC antibodies were detected more frequently in the clinical influenza group than the subclinical group. In addition, in contrast to HAI and CDL antibodies, HAI and the ADCC antibodies titers did not correlate. We also found that ADCC, but not CDL or HAI antibodies, positively correlated with the ages of the children.

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Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses

Cited by 120 publications

References 39 publications

Complement-Dependent Lysis of Influenza A Virus-Infected Cells by Broadly Cross-Reactive Human Monoclonal Antibodies

Complement-Dependent Lysis of Influenza A Virus-Infected Cells by Broadly Cross-Reactive Human Monoclonal Antibodies

Structure of the Extracellular Domain of Matrix Protein 2 of Influenza A Virus in Complex with a Protective Monoclonal Antibody

Relationship of Preexisting Influenza Hemagglutination Inhibition, Complement-Dependent Lytic, and Antibody-Dependent Cellular Cytotoxicity Antibodies to the Development of Clinical Illness in a Prospective Study of A(H1N1)pdm09 Influenza in Children

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