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

Nature Medicine volume 15, pages 34–41 (2009)Cite this article

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.

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Authors and Affiliations

  1. INFANT Foundation, Gavilan 94, Buenos Aires, 1406, Argentina

    Maria Florencia Delgado, Silvina Coviello, A Clara Monsalvo, Guillermina A Melendi, Johanna Zea Hernandez, Juan P Batalle, Leandro Diaz, Pablo M Irusta & Fernando P Polack

  2. Department of Pediatrics, School of Medicine, Johns Hopkins University, 200 North Wolfe Street

    Guillermina A Melendi, Johanna Zea Hernandez & Fernando P Polack

  3. Baltimore, 21205, Maryland, USA

    Guillermina A Melendi, Johanna Zea Hernandez & Fernando P Polack

  4. Instituto de Salud Carlos III and CIBER de Enfermedades Respiratorias, Pozuelo km.2, 28220, Madrid, Majadahonda, Spain

    Alfonsina Trento & José A Melero

  5. Department of Environmental Health, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, 21205, Maryland, USA

    Herng-Yu Chang & Wayne Mitzner

  6. Rockefeller University, 1230 York Avenue, New York, 10065, New York, USA

    Jeffrey Ravetch

  7. Department of Human Science, Georgetown University, 3700 Reservoir Road, Washington, 20007, DC, USA

    Pablo M Irusta

  8. Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, 21205, Maryland, USA

    Fernando P Polack

  9. Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, 21205, Maryland, USA

    Fernando P Polack

Authors
  1. Maria Florencia Delgado
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  2. Silvina Coviello
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Contributions

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.

Corresponding author

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). https://doi.org/10.1038/nm.1894

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