title: Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease.
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.
authors.affiliation: INFANT Foundation, Gavilan 94, Buenos Aires, Argentina.
authors.forename: Maria Florencia
authors.initials: MF
authors.lastname: Delgado
authors.forename: Silvina
authors.initials: S
authors.lastname: Coviello
authors.forename: A Clara
authors.initials: AC
authors.lastname: Monsalvo
authors.forename: Guillermina A
authors.initials: GA
authors.lastname: Melendi
authors.forename: Johanna Zea
authors.initials: JZ
authors.lastname: Hernandez
authors.forename: Juan P
authors.initials: JP
authors.lastname: Batalle
authors.forename: Leandro
authors.initials: L
authors.lastname: Diaz
authors.forename: Alfonsina
authors.initials: A
authors.lastname: Trento
authors.forename: Herng-Yu
authors.initials: HY
authors.lastname: Chang
authors.forename: Wayne
authors.initials: W
authors.lastname: Mitzner
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ravetch
authors.forename: José A
authors.initials: JA
authors.lastname: Melero
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Irusta
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Polack
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000276:immunology; D018450:Disease Progression; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D018357:Respiratory Syncytial Virus Infections / Q000150:complications* / Q000276:immunology / Q000628:therapy*; D022261:Respiratory Syncytial Virus Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D051193:Toll-Like Receptors / Q000276:immunology*; D017211:Treatment Failure; D015164:Vaccines, Inactivated / Q000276:immunology / Q000627:therapeutic use; D014779:Virus Replication / Q000502:physiology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D022261:Respiratory Syncytial Virus Vaccines; D051193:Toll-Like Receptors; D015164:Vaccines, Inactivated