Lack of Antibody Affinity Maturation Due to Poor Toll-like Receptor Stimulation Leads to Enhanced Respiratory Syncytial Virus Disease

Nat Med. 2009 Jan;15(1):34-41. doi: 10.1038/nm.1894. Epub 2008 Dec 14.

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.

Publication types

  • Comparative Study
  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Affinity* / immunology
  • Disease Progression
  • Immunotherapy / adverse effects
  • Immunotherapy / methods
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Respiratory Syncytial Virus Infections / complications*
  • Respiratory Syncytial Virus Infections / immunology
  • Respiratory Syncytial Virus Infections / therapy*
  • Respiratory Syncytial Virus Vaccines / adverse effects
  • Respiratory Syncytial Virus Vaccines / immunology
  • Respiratory Syncytial Virus Vaccines / therapeutic use*
  • Toll-Like Receptors / immunology*
  • Treatment Failure
  • Vaccines, Inactivated / immunology
  • Vaccines, Inactivated / therapeutic use
  • Virus Replication / physiology

Substances

  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Respiratory Syncytial Virus Vaccines
  • Toll-Like Receptors
  • Vaccines, Inactivated