Safety and Immunogenicity of Escherichia coli 018 O-Specific Polysaccharide (O-PS)-Toxin A and O-PS-Cholera Toxin Conjugate Vaccines in Humans

Abstract

O-specific polysaccharide (O-PS) isolated from serotype 18 Escherichia coli lipopolysaccharide (LPS) was covalently coupled to either Pseudomonas aeruginosa toxin A (TA) or or cholera toxin (CT). The conjugates were nontoxic and nonpyrogenic. The conjugates were well tolerated on parenteral administration to human volunteers, with only mild, transient local reactions reported. Immunization engendered an IgG antibody response to both the O-PS and carrier protein. Anti-LPS antibody promoted the uptake and killing of an E. coli O18 strain bearing the K1 capsule by human polymorphonuclear leukocytes, which was complement dependent. Antibody to carrier protein neutralized the activity of native TA or CT in cell culture assays. Passively transferred IgG isolated from the serum of immunized donors provided a significant (P less than .01) degree of protection against fatal experimental E. coli O18 sepsis in mice. This study illustrates the potential use of such conjugates as vaccines against E. coli extraintestinal infections.

Estimation of protective levels of anti-O-specific lipopolysaccharide immunoglobulin G antibody against experimental Escherichia coli infection

“…Human anti-018 PS IgG isolation. Pre-and postvaccination human anti-018 PS sera were obtained as described previously (6). IgG was isolated by use of a QAE/Sephadex column as previously described (12).…”

“…This conjugate vaccine was found to be nontoxic and nonpyrogenic (6). The immunogenicity of the 018 PS-TA conjugate vaccine was previously demonstrated with an enzyme-linked immunosorbent assay (ELISA) (5,6). In the present study, in an attempt to estimate protective levels of specific anti-018 LPS antibody in a neonatal rat model, we correlated serum anti-018 LPS immunoglobulin G (IgG) concentrations derived from the 018 PS-TA conjugate vaccine with in vivo protection against bacteremia and death caused by E. coli Kl.…”

“…Most human E. coli blood isolates fall within a small number of 0 serotypes; 018 lipopolysaccharide (LPS) is the serotype most frequently associated with bacteremia (3,15,19). Because of these findings, a prototype 0 polysaccharide (PS)-protein conjugate vaccine comprising 018 PS without lipid A conjugated to toxin A (TA) of Pseudomonas aeruginosa was developed (5,6). This conjugate vaccine was found to be nontoxic and nonpyrogenic (6).…”

“…Because of these findings, a prototype 0 polysaccharide (PS)-protein conjugate vaccine comprising 018 PS without lipid A conjugated to toxin A (TA) of Pseudomonas aeruginosa was developed (5,6). This conjugate vaccine was found to be nontoxic and nonpyrogenic (6). The immunogenicity of the 018 PS-TA conjugate vaccine was previously demonstrated with an enzyme-linked immunosorbent assay (ELISA) (5,6).…”

Endotoxin immunization

“…Many studies have shown that an endotoxin vaccine can be made from parts of the O-polysacharide [49] or core [50] components and that subjects mount an antibody response against the antigens given. However as described above, the trials of anti-lipid A monoclonal antibodies E5 and HA-1A in sepsis failed to prospectively show a reduction in mortality.…”