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Journal of Virology, November 2002, p. 11561-11569, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11561-11569.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Immunization of Macaques with Formalin-Inactivated Respiratory Syncytial Virus (RSV) Induces Interleukin-13-Associated Hypersensitivity to Subsequent RSV Infection

Rik L. de Swart,1* Thijs Kuiken,1 Helga H. Timmerman,1 Geert van Amerongen,2 Bernadette G. van den Hoogen,1 Helma W. Vos,1 Herman J. Neijens,3 Arno C. Andeweg,1 and Albert D. M. E. Osterhaus1

Institute of Virology,1 Department of Pediatrics, Erasmus MC, 3000 DR Rotterdam,3 National Institute of Public Health and the Environment, 3720 BA Bilthoven, The Netherlands2

Received 15 April 2002/ Accepted 12 August 2002

Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and the elderly. RSV vaccine development has been hampered by results of clinical trials in the 1960s, when formalin-inactivated whole-RSV preparations adjuvated with alum (FI-RSV) were found to predispose infants for enhanced disease following subsequent natural RSV infection. We have reproduced this apparently immunopathological phenomenon in infant cynomolgus macaques and identified immunological and pathological correlates. Vaccination with FI-RSV induced specific virus-neutralizing antibody responses accompanied by strong lymphoproliferative responses. The vaccine-induced RSV-specific T cells predominantly produced the Th2 cytokines interleukin-13 (IL-13) and IL-5. Intratracheal challenge with a macaque-adapted wild-type RSV 3 months after the third vaccination elicited a hypersensitivity response associated with lung eosinophilia. The challenge resulted in a rapid boosting of IL-13-producing T cells in the FI-RSV-vaccinated animals but not in the FI-measles virus-vaccinated control animals. Two out of seven FI-RSV-vaccinated animals died 12 days after RSV challenge with pulmonary hyperinflation. Surprisingly, the lungs of these two animals did not show overt inflammatory lesions. However, upon vaccination the animals had shown the strongest lymphoproliferative responses associated with the most pronounced Th2 phenotype within their group. We hypothesize that an IL-13-associated asthma-like mechanism resulted in airway hyperreactivity in these animals. This nonhuman primate model will be an important tool to assess the safety of nonreplicating candidate RSV vaccines.

* Corresponding author. Mailing address: Institute of Virology, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Phone: 31 10 4088280. Fax: 31 10 4089485. E-mail: deswart{at}viro.fgg.eur.nl.

Journal of Virology, November 2002, p. 11561-11569, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11561-11569.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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