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Mucosal Delivery of a Respiratory Syncytial Virus CTL Peptide with Enterotoxin-Based Adjuvants Elicits Protective, Immunopathogenic, and Immunoregulatory Antiviral CD8⁺ T Cell Responses¹

Cameron P. Simmons^2,*, Tracy Hussell, Tim Sparer, Gerhard Walzl, Peter Openshaw and Gordon Dougan^*

^* Department of Biochemistry, Imperial College of Science, Technology and Medicine, South Kensington, London, United Kingdom; and Department of Respiratory Medicine, St. Mary’s Medical School, Paddington, London, United Kingdom

In an effort to develop a safe and effective vaccine against respiratory syncytial virus (RSV), we used Escherichia coli heat-labile toxin (LT), and LTK63 (an LT mutant devoid of ADP-ribosyltransferase activity) to elicit murine CD8⁺ CTL responses to an intranasally codelivered CTL peptide from the second matrix protein (M2) of RSV. M2_82–90-specific CD8⁺ T cells were detected by IFN- enzyme-linked immunospot and ⁵¹Cr release assay in local and systemic lymph nodes, and their induction was dependent on the use of a mucosal adjuvant. CTL elicited by peptide immunization afforded protection against RSV challenge, but also enhanced weight loss. CTL-mediated viral clearance was not dependent on IFN- since depletion using specific mAb during RSV challenge did not affect cellular recruitment or viral clearance. Depletion of IFN- did, however, reduce the concentration of TNF detected in lung homogenates of challenged mice and largely prevented the weight loss associated with CTL-mediated viral clearance. Mice primed with the attachment glycoprotein (G) develop lung eosinophilia after intranasal RSV challenge. Mucosal peptide vaccination reduced pulmonary eosinophilia in mice subsequently immunized with G and challenged with RSV. These studies emphasize that protective and immunoregulatory CD8⁺ CTL responses can be mucosally elicited using enterotoxin-based mucosal adjuvants but that resistance against viral infection may be accompanied by enhanced disease.

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