The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/8/681/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 4, August 17, 1998 681-688

Articles

Protection against Respiratory Syncytial Virus Infection by DNA Immunization

Xiaomao Li, Suryaprakash Sambhara, Cindy Xin Li, Mary Ewasyshyn, Mark Parrington, Judy Caterini, Olive James, George Cates, Run-Pan Du, and Michel Klein

From the Research Centre, Pasteur Mérieux Connaught Canada, North York, Ontario, Canada M2R 3T4

Respiratory syncytial virus (RSV) remains a major cause of morbidity and mortality in infants and the elderly and is a continuing challenge for vaccine development. A murine T helper cell (Th) type 2 response associates with enhanced lung pathology, which has been observed in past infant trials using formalin-inactivated RSV vaccine. In this study, we have engineered an optimized plasmid DNA vector expressing the RSV fusion (F) protein (DNA-F). DNA-F was as effective as live RSV in mice at inducing neutralizing antibody and cytotoxic T lymphocyte responses, protection against infection, and high mRNA expression of lung interferon {gamma} after viral challenge. Furthermore, a DNA-F boost could switch a preestablished anti-RSV Th2 response towards a Th1 response. Critical elements for the optimization of the plasmid constructs included expression of a secretory form of the F protein and the presence of the rabbit β-globin intron II sequence upstream of the F-encoding sequence. In addition, anti-F systemic immune response profile could be modulated by the route of DNA-F delivery: intramuscular immunization resulted in balanced responses, whereas intradermal immunization resulted in a Th2 type of response. Thus, DNA-F immunization may provide a novel and promising RSV vaccination strategy.

Key Words: respiratory syncytial virus • DNA vaccine • vector design • F protein • immune modulation

Address correspondence to Xiaomao Li, Research Centre, Pasteur Mérieux Connaught Canada, 1755 Steeles Ave. West, North York, Ontario, Canada M2R 3T4. Phone: 416-667-2976; Fax: 416-661-7960; E-mail: xli{at}ca.pmc-vacc.com

We wish to express our sincere appreciation to Nancy Scollard and Anjna Kurichh for their expertise in viral and CTL assays, and to Bill Bradley and Diane England for oligonucleotide synthesis and DNA sequencing. We also wish to thank Dr. Raymond Oomer and Shahneela Usman for the purification of the RSV F protein. We are grateful to Dr. David Brownstein (Yale University, New Haven, CT), who evaluated the lung histopathology.

Abbreviations used: BC cells, Balb/c fibroblasts; DNA-F, optimized plasmid DNA vector expressing the RSV F protein; FI-RSV, formalin-inactivated RSV; F protein, fusion protein; RSV, respiratory syncytial virus.


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