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Influenza hemagglutinin stem-fragment immunogen elicits broadly neutralizing antibodies and confers heterologous protection.
Mallajosyula, Vamsee V A; Citron, Michael; Ferrara, Francesca; Lu, Xianghan; Callahan, Cheryl; Heidecker, Gwendolyn J; Sarma, Siddhartha P; Flynn, Jessica A; Temperton, Nigel J; Liang, Xiaoping; Varadarajan, Raghavan.
Afiliação
  • Mallajosyula VV; Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India;
  • Citron M; Merck Research Laboratories, West Point, PA 19486; and.
  • Ferrara F; Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent, Chatham Maritime ME4 4TB, United Kingdom.
  • Lu X; Merck Research Laboratories, West Point, PA 19486; and.
  • Callahan C; Merck Research Laboratories, West Point, PA 19486; and.
  • Heidecker GJ; Merck Research Laboratories, West Point, PA 19486; and.
  • Sarma SP; Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India;
  • Flynn JA; Merck Research Laboratories, West Point, PA 19486; and.
  • Temperton NJ; Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent, Chatham Maritime ME4 4TB, United Kingdom.
  • Liang X; Merck Research Laboratories, West Point, PA 19486; and varadar@mbu.iisc.ernet.in liangxiaoping@walvax.com.
  • Varadarajan R; Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India; varadar@mbu.iisc.ernet.in liangxiaoping@walvax.com.
Proc Natl Acad Sci U S A ; 111(25): E2514-23, 2014 Jun 24.
Article em En | MEDLINE | ID: mdl-24927560
ABSTRACT
Influenza hemagglutinin (HA) is the primary target of the humoral response during infection/vaccination. Current influenza vaccines typically fail to elicit/boost broadly neutralizing antibodies (bnAbs), thereby limiting their efficacy. Although several bnAbs bind to the conserved stem domain of HA, focusing the immune response to this conserved stem in the presence of the immunodominant, variable head domain of HA is challenging. We report the design of a thermotolerant, disulfide-free, and trimeric HA stem-fragment immunogen which mimics the native, prefusion conformation of HA and binds conformation specific bnAbs with high affinity. The immunogen elicited bnAbs that neutralized highly divergent group 1 (H1 and H5 subtypes) and 2 (H3 subtype) influenza virus strains in vitro. Stem immunogens designed from unmatched, highly drifted influenza strains conferred robust protection against a lethal heterologous A/Puerto Rico/8/34 virus challenge in vivo. Soluble, bacterial expression of such designed immunogens allows for rapid scale-up during pandemic outbreaks.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por Orthomyxoviridae / Glicoproteínas de Hemaglutininação de Vírus da Influenza / Vírus da Influenza A Subtipo H1N1 / Anticorpos Neutralizantes / Anticorpos Antivirais Limite: Animals Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por Orthomyxoviridae / Glicoproteínas de Hemaglutininação de Vírus da Influenza / Vírus da Influenza A Subtipo H1N1 / Anticorpos Neutralizantes / Anticorpos Antivirais Limite: Animals Idioma: En Ano de publicação: 2014 Tipo de documento: Article