Protection against respiratory syncytial virus infection by DNA immunization.
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 beta-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.
Li
X
X
Research Centre, Pasteur Mérieux Connaught Canada, North York, Ontario, Canada M2R 3T4. xli@ca.pmc-vacc.com
Sambhara
S
S
Li
C X
CX
Ewasyshyn
M
M
Parrington
M
M
Caterini
J
J
James
O
O
Cates
G
G
Du
R P
RP
Klein
M
M
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005822:Genetic Vectors; D015707:HN Protein; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids; D011817:Rabbits; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000517:prevention & control*; D018113:Respiratory Syncytial Virus, Human / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology*
D000914:Antibodies, Viral; D000956:Antigens, Viral; D015707:HN Protein; D015848:Interleukin-5; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; D014764:Viral Proteins; D014765:Viral Vaccines; C116204:attachment protein G; D015847:Interleukin-4; D007371:Interferon-gamma