Salmonella typhi and S typhimurium derivatives harbouring deletions in aromatic biosynthesis and Salmonella Pathogenicity Island-2 (SPI-2) genes as vaccines and vectors.
The S. typhimurium strain (TML deltaaroC deltassaV) WT05, harbouring defined deletions in genes involved in both the aromatic biosynthesis pathway (aroC) and the Salmonella Pathogenicity Island-2 (SPI-2) (ssaV) was shown to be significantly attenuated in C57 BL/6 interferon gamma knockout mice following oral inoculation. Similarly, the S. typhi strain (Ty2 deltaaroC deltassaV) ZH9 harbouring the aroC and ssaV mutations propagated less efficiently than wild type in human macrophages. These studies demonstrated the attractive safety profile of the aroC ssaV mutant combination. Strains S. typhimurium (TML deltaaroC deltassaV ) WT05 and S. typhi (Ty2 deltaaroC deltassaV) ZH9 were subsequently tested as vaccine vectors to deliver E. coli heat-labile toxin (LT-B) mucosally to mice. Mice inoculated orally with S. typhimurium (TML deltaaroC deltassaV) WT05 expressing LT-B (WT05/LT-B) elicited high titres of both LT-specific serum IgG and intestinal IgA, although no specific IgA was detected in the vagina. Similarly, intranasal inoculation of mice with S. typhi (Ty2 deltaaroC deltassaV) ZH9 expressing LT-B (ZH9/LT-B) elicited even higher titres of LT-specific serum antibody as well as LT-specific Ig in the vagina. We conclude that deltaaroC deltassaV strains of Salmonella are highly attenuated and are promising candidates both as human typhoid vaccines and as vaccine vectors for the delivery of heterologous antigens.
Khan
Shahid A
SA
Microscience Limited, 545 Eskdale Road, Winnersh Triangle, Wokingham, Berkshire RG41 5TU, UK. s.khan@microscience.com
Stratford
Richard
R
Wu
Tao
T
Mckelvie
Nicola
N
Bellaby
Trevor
T
Hindle
Zoe
Z
Sinha
Katharine A
KA
Eltze
Shayne
S
Mastroeni
Piero
P
Pickard
Derek
D
Dougan
Gordon
G
Chatfield
Steven N
SN
Brennan
Frank R
FR
D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology*; D001427:Bacterial Toxins / Q000096:biosynthesis / Q000276:immunology; D001428:Bacterial Vaccines / Q000276:immunology*; D002470:Cell Survival; D004768:Enterotoxins / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D029968:Escherichia coli Proteins; D005260:Female; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000378:metabolism*; D018928:Immunity, Mucosal / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology; D007422:Intestines / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D012485:Salmonella typhi / Q000235:genetics* / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics* / Q000276:immunology*; D014621:Vagina / Q000276:immunology
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D001428:Bacterial Vaccines; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D006841:Hydrocarbons, Aromatic; D007074:Immunoglobulin G; D008565:Membrane Proteins; C440638:SPI-2 protein, Salmonella; D007371:Interferon-gamma; C027538:heat-labile enterotoxin, E coli