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

Maria Florencia Delgado, Silvina Coviello, A. Clara Monsalvo, Guillermina A. Melendi, Johanna Zea Hernandez, Juan P. Batalle, Leandro Diaz, Alfonsina Trento, Herng Yu Chang, Wayne Mitzner, Jeffrey Ravetch, José A. Melero, Pablo M. Irusta, Fernando P. Polack

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)34-41
Number of pages8
JournalNature medicine
Volume15
Issue number1
DOIs
StatePublished - Jan 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Delgado, M. F., Coviello, S., Monsalvo, A. C., Melendi, G. A., Hernandez, J. Z., Batalle, J. P., Diaz, L., Trento, A., Chang, H. Y., Mitzner, W., Ravetch, J., Melero, J. A., Irusta, P. M., & Polack, F. P. (2009). Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nature medicine, 15(1), 34-41. https://doi.org/10.1038/nm.1894