Mucosal DNA vaccine immunization against measles with a highly attenuated Shigella flexneri vector.
An intranasal vaccine vector would elicit protective immunity at the respiratory mucosa, the portal of entry and the primary site for replication for measles virus (MV) and other respiratory viruses. In a murine model of pulmonary Shigella, we demonstrate here that a candidate-attenuated Shigella vaccine vector is safely tolerated in IFN-gamma deficient mice at an inoculum that is 1 million-fold higher than the inoculum of the wild-type parent strain that would be lethal for greater than 90% of these mice. Also, following intranasal inoculation, the Deltaasd Shigella harboring a DNA MV vaccine plasmid induces a vigorous MV-specific Th1-type (both CD8+ CTL and IFN-gamma) and, to a lesser degree, Th2-type responses among splenocytes in addition to low levels of IgG and IgA in the serum. Priming for MV-specific CTL responses was possible in mice that had prior infection with a wild-type Shigella of the same serotype. Remarkably, mice immunized by the intranasal route with attenuated Shigella harboring the DNA MV vaccine plasmid had a level of MV-specific CTL activity among splenocytes that was comparable with levels observed in mice immunized by the i.p. route with attenuated Salmonella typhi harboring the same DNA vaccine plasmid, despite the fact that Shigella remained localized to the lungs, yet Salmonella disseminated to the spleen following inoculation. Thus, Deltaasd Shigella represents a very useful vector for delivery of DNA vaccines to mucosal lymphoid tissues.
Fennelly
G J
GJ
Department of Pediatrics, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA. fennelly@aecom.yu.edu
Khan
S A
SA
Abadi
M A
MA
Wild
T F
TF
Bloom
B R
BR
D000281:Administration, Intranasal; D000818:Animals; D000956:Antigens, Viral / Q000008:administration & dosage / Q000235:genetics; D015870:Gene Expression; D005822:Genetic Vectors; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000473:pathology; D008458:Measles Vaccine / Q000008:administration & dosage* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D009154:Mutation; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000235:genetics / Q000276:immunology; D012449:Safety; D012763:Shigella flexneri / Q000235:genetics* / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology