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

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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.

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Figure 1: Nonreplicating vaccines against RSV prime for ERD.
Figure 2: Nonreplicating vaccine elicits non-protective, low avidity antibody.
Figure 3: Affinity is crucial for protection against RSV.
Figure 4: Adaptive immunity after inactivated vaccines.
Figure 5: Deficient activation of TLRs by inactivated vaccines.
Figure 6: UVRSV plus TLR agonists protects against ERD.

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Acknowledgements

PFP was a generous gift from V. Randolph (Wyeth Lederle) and Gk2.43 monoclonal antibody for CD8+ T lymphocyte depletion was generously provided by B. Graham and T. Johnson (National Institute of Allergy and Infectious Diseases, US National Institutes of Health). We thank M. del Carmen Puggioli for excellent technical assistance. This work was supported by AI-054952 (F.P.P.) and the Thomas and Carol McCann Innovative Research Fund for Asthma and Respiratory Diseases (F.P.P.). M.F.D., A.C.M., J.P.B. and S.C. are recipients of Doctoral Awards from the Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. G.A.M. is a recipient of the Thrasher Research Fund Early Career Award.

Author information

M.F.D., S.C., A.C.M., G.A.M., J.Z.H., J.P.B., L.D., A.T. and H.-Y.C. performed research; J.R., J.A.M. and W.M. contributed new reagents and/or analytic tools; M.F.D., W.M., J.A.M., J.P.B., P.M.I. and F.P.P. analyzed data; F.P.P. designed research; M.F.D., P.M.I. and F.P.P. wrote the paper.

Correspondence to Fernando P Polack.

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Delgado, M., Coviello, S., Monsalvo, A. et al. Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nat Med 15, 34–41 (2009) doi:10.1038/nm.1894

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