Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease

Autores
Delgado, Maria Florencia; Coviello, Silvina Andrea; Monsalvo, Ana Clara; Melendi, Guillermina Amanda; Hernandez, Johanna Zea; Batalle, Juan Pio; Diaz, Leandro; Trento, Alfonsina; Chang, Herng-Yu; Mitzner, Wayne; Ravetch, Jeffrey; Melero, José A.; Irusta, Pablo M.; Polack, Fernando Pedro
Año de publicación
2009
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants.
Fil: Delgado, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina
Fil: Coviello, Silvina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina
Fil: Monsalvo, Ana Clara. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Melendi, Guillermina Amanda. Fundación para la Investigación en Infectología Infantil; Argentina. University Johns Hopkins; Estados Unidos
Fil: Hernandez, Johanna Zea. Fundación para la Investigación en Infectología Infantil; Argentina. University Johns Hopkins; Estados Unidos
Fil: Batalle, Juan Pio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina
Fil: Diaz, Leandro. Fundación para la Investigación en Infectología Infantil; Argentina
Fil: Trento, Alfonsina. Universidad Carlos III de Madrid. Instituto de Salud; España
Fil: Chang, Herng-Yu. University Johns Hopkins; Estados Unidos
Fil: Mitzner, Wayne. University Johns Hopkins; Estados Unidos
Fil: Ravetch, Jeffrey. The Rockefeller University; Estados Unidos
Fil: Melero, José A.. Universidad Carlos III de Madrid. Instituto de Salud; España
Fil: Irusta, Pablo M.. University Of Georgetown; Estados Unidos. Fundación para la Investigación en Infectología Infantil; Argentina
Fil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; Argentina. University Johns Hopkins; Estados Unidos
Materia
RSV
FIRSV
TLR
Antibodies
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/96246
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/96246
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus diseaseDelgado, Maria FlorenciaCoviello, Silvina AndreaMonsalvo, Ana ClaraMelendi, Guillermina AmandaHernandez, Johanna ZeaBatalle, Juan PioDiaz, LeandroTrento, AlfonsinaChang, Herng-YuMitzner, WayneRavetch, JeffreyMelero, José A.Irusta, Pablo M.Polack, Fernando PedroRSVFIRSVTLRAntibodieshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants.Fil: Delgado, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Coviello, Silvina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Monsalvo, Ana Clara. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Melendi, Guillermina Amanda. Fundación para la Investigación en Infectología Infantil; Argentina. University Johns Hopkins; Estados UnidosFil: Hernandez, Johanna Zea. Fundación para la Investigación en Infectología Infantil; Argentina. University Johns Hopkins; Estados UnidosFil: Batalle, Juan Pio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Diaz, Leandro. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Trento, Alfonsina. Universidad Carlos III de Madrid. Instituto de Salud; EspañaFil: Chang, Herng-Yu. University Johns Hopkins; Estados UnidosFil: Mitzner, Wayne. University Johns Hopkins; Estados UnidosFil: Ravetch, Jeffrey. The Rockefeller University; Estados UnidosFil: Melero, José A.. Universidad Carlos III de Madrid. Instituto de Salud; EspañaFil: Irusta, Pablo M.. University Of Georgetown; Estados Unidos. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; Argentina. University Johns Hopkins; Estados UnidosNature Publishing Group2009-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/96246Delgado, Maria Florencia; Coviello, Silvina Andrea; Monsalvo, Ana Clara; Melendi, Guillermina Amanda; Hernandez, Johanna Zea; et al.; Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease; Nature Publishing Group; Nature Medicine; 15; 1; 1-2009; 34-411078-8956CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/nm.1894info:eu-repo/semantics/altIdentifier/doi/10.1038/nm.1894info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:39:53Zoai:ri.conicet.gov.ar:11336/96246instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:39:53.571CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease
title Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease
spellingShingle Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease
Delgado, Maria Florencia
RSV
FIRSV
TLR
Antibodies
title_short Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease
title_full Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease
title_fullStr Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease
title_full_unstemmed Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease
title_sort Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease
dc.creator.none.fl_str_mv Delgado, Maria Florencia
Coviello, Silvina Andrea
Monsalvo, Ana Clara
Melendi, Guillermina Amanda
Hernandez, Johanna Zea
Batalle, Juan Pio
Diaz, Leandro
Trento, Alfonsina
Chang, Herng-Yu
Mitzner, Wayne
Ravetch, Jeffrey
Melero, José A.
Irusta, Pablo M.
Polack, Fernando Pedro
author Delgado, Maria Florencia
author_facet Delgado, Maria Florencia
Coviello, Silvina Andrea
Monsalvo, Ana Clara
Melendi, Guillermina Amanda
Hernandez, Johanna Zea
Batalle, Juan Pio
Diaz, Leandro
Trento, Alfonsina
Chang, Herng-Yu
Mitzner, Wayne
Ravetch, Jeffrey
Melero, José A.
Irusta, Pablo M.
Polack, Fernando Pedro
author_role author
author2 Coviello, Silvina Andrea
Monsalvo, Ana Clara
Melendi, Guillermina Amanda
Hernandez, Johanna Zea
Batalle, Juan Pio
Diaz, Leandro
Trento, Alfonsina
Chang, Herng-Yu
Mitzner, Wayne
Ravetch, Jeffrey
Melero, José A.
Irusta, Pablo M.
Polack, Fernando Pedro
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv RSV
FIRSV
TLR
Antibodies
topic RSV
FIRSV
TLR
Antibodies
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants.
Fil: Delgado, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina
Fil: Coviello, Silvina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina
Fil: Monsalvo, Ana Clara. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Melendi, Guillermina Amanda. Fundación para la Investigación en Infectología Infantil; Argentina. University Johns Hopkins; Estados Unidos
Fil: Hernandez, Johanna Zea. Fundación para la Investigación en Infectología Infantil; Argentina. University Johns Hopkins; Estados Unidos
Fil: Batalle, Juan Pio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina
Fil: Diaz, Leandro. Fundación para la Investigación en Infectología Infantil; Argentina
Fil: Trento, Alfonsina. Universidad Carlos III de Madrid. Instituto de Salud; España
Fil: Chang, Herng-Yu. University Johns Hopkins; Estados Unidos
Fil: Mitzner, Wayne. University Johns Hopkins; Estados Unidos
Fil: Ravetch, Jeffrey. The Rockefeller University; Estados Unidos
Fil: Melero, José A.. Universidad Carlos III de Madrid. Instituto de Salud; España
Fil: Irusta, Pablo M.. University Of Georgetown; Estados Unidos. Fundación para la Investigación en Infectología Infantil; Argentina
Fil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; Argentina. University Johns Hopkins; Estados Unidos
description Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants.
publishDate 2009
dc.date.none.fl_str_mv 2009-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/96246
Delgado, Maria Florencia; Coviello, Silvina Andrea; Monsalvo, Ana Clara; Melendi, Guillermina Amanda; Hernandez, Johanna Zea; et al.; Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease; Nature Publishing Group; Nature Medicine; 15; 1; 1-2009; 34-41
1078-8956
CONICET Digital
CONICET
url http://hdl.handle.net/11336/96246
identifier_str_mv Delgado, Maria Florencia; Coviello, Silvina Andrea; Monsalvo, Ana Clara; Melendi, Guillermina Amanda; Hernandez, Johanna Zea; et al.; Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease; Nature Publishing Group; Nature Medicine; 15; 1; 1-2009; 34-41
1078-8956
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/nm.1894
info:eu-repo/semantics/altIdentifier/doi/10.1038/nm.1894
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.069144

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