RESUMO
Better vaccines against influenza virus are urgently needed to provide broader protection against diverse strains, subtypes, and types. Such efforts are assisted by the identification of novel broadly neutralizing epitopes targeted by protective antibodies. Influenza vaccine development has largely focused on the hemagglutinin, but the other major surface antigen, the neuraminidase, has reemerged as a potential target for universal vaccines. We describe three human monoclonal antibodies isolated from an H3N2-infected donor that bind with exceptional breadth to multiple different influenza A and B virus neuraminidases. These antibodies neutralize the virus, mediate effector functions, are broadly protective in vivo, and inhibit neuraminidase activity by directly binding to the active site. Structural and functional characterization of these antibodies will inform the development of neuraminidase-based universal vaccines against influenza virus.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Neuraminidase/imunologia , Proteínas Virais/imunologia , Adulto , Animais , Domínio Catalítico , Linhagem Celular , Epitopos/imunologia , Feminino , Humanos , Imunização Passiva , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A/enzimologia , Vírus da Influenza B/enzimologia , Vacinas contra Influenza , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Testes de Neutralização , Estrutura Quaternária de ProteínaRESUMO
Induction of an antibody response capable of recognizing highly diverse strains is a major obstacle to the development of vaccines for viruses such as HIV and influenza. Here, we report the dynamics of B cell expansion and evolution at the single-cell level after vaccination with a replication-competent adenovirus type 4 recombinant virus expressing influenza H5 hemagglutinin. Fluorescent H1 or H5 probes were used to quantitate and isolate peripheral blood B cells and their antigen receptors. We observed increases in H5-specific antibody somatic hypermutation and potency for several months beyond the period of active viral replication that was not detectable at the serum level. Individual broad and potent antibodies could be isolated, including one stem-specific antibody that is part of a new multidonor class. These results demonstrate prolonged evolution of the B cell response for months after vaccination and should be considered in efforts to evaluate or boost vaccine-induced immunity.
Assuntos
Adenoviridae/genética , Linfócitos B/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Adenoviridae/imunologia , Administração Oral , Adolescente , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Feminino , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Imunogenicidade da Vacina , Virus da Influenza A Subtipo H5N1/genética , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Hipermutação Somática de Imunoglobulina/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Replicação Viral/imunologia , Adulto JovemRESUMO
Three cases of influenza A(H10N8) virus infection in humans have been reported; 2 of these infected persons died. Characterization of the receptor binding pattern of H10 hemagglutinin from avian and human isolates showed that both interact weakly with human-like receptors and maintain strong affinity for avian-like receptors.
