AroD deletion attenuates Shigella flexneri strain 2457T and makes it a safe and efficacious oral vaccine in monkeys.
The aromatic-dependent live Shigella flexneri 2a vaccine strain SFL1070, with a deleted aroD gene, had a much reduced intracellular growth in HeLa cells compared with its parent strain S. flexneri 2457T. S. flexneri SFL1070 gave no adverse effects in eight Macaca fascicularis monkeys orally vaccinated with four doses of 1 x 10(11) live bacteria within a 5-week period, whereas S. flexneri 2457T caused dysentery in all eight non-vaccinated monkeys. Thus the aromatic dependency rendered S. flexneri SFL1070 significantly attenuated (p = 0.00008). Significant intestinal S. flexneri lipopolysaccharide (LPS)-specific sIgA responses were seen in seven of eight vaccinated monkeys (p < 0.01) after four doses with SFL1070. However, serum IgG or IgA responses to various S. flexneri LPS antigens and the invasion plasmid antigens (Ipa-s) were seen in only four of eight vaccinated monkeys. The serum IgG titre increases against S. flexneri Y and 2a LPS reached significant levels (p < or = 0.05). All but one of the vaccinated monkeys were protected against oral challenge with 1 x 10(10) or 1 x 10(11) live S. flexneri 2457T given 2 weeks after the last vaccination. The protection was highly significant (p = 0.0007) as all non-vaccinated monkeys challenged with equal doses of strain 2457T developed dysentery. Three of them succumbed. Challenge infection of vaccinated monkeys elicited serum IgA and IgG responses to the homologous S. flexneri 2a LPS in three monkeys each (0.005 < or = p < or = 0.025). Serum IgA and IgG responses to the Ipa-s were seen in five and four monkeys each (0.01 < p < or = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Kärnell
A
A
Karolinska Institute, Department of Clinical Bacteriology, Huddinge Hospital, Sweden.
Cam
P D
PD
Verma
N
N
Lindberg
A A
AA
D000284:Administration, Oral; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000942:Antigens, Bacterial / Q000494:pharmacology; D001426:Bacterial Proteins; D001428:Bacterial Vaccines / Q000235:genetics* / Q000494:pharmacology* / Q000633:toxicity; D004405:Dysentery, Bacillary / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D017353:Gene Deletion; D005798:Genes, Bacterial / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007422:Intestines / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D012763:Shigella flexneri / Q000235:genetics* / Q000254:growth & development / Q000276:immunology*; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000235:genetics* / Q000494:pharmacology* / Q000633:toxicity
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; C063664:IpaA protein, Shigella flexneri; D008070:Lipopolysaccharides; D014613:Vaccines, Attenuated