title: Safety and immunogenicity of improved Shigella O-specific polysaccharide-protein conjugate vaccines in adults in Israel.
abstract: Data suggest that the O-specific polysaccharide (O-SP) domain of the lipopolysaccharide (LPS) of Shigella species is both an essential virulence factor and a protective antigen and that a critical level of serum immunoglobulin G (IgG) to this antigen will confer immunity to shigellosis. Because covalent attachment of polysaccharides to proteins increases their immunogenicity, especially in infants and in young children, the O-SP of Shigella species were bound to medically useful proteins, and the safety and immunogenicity of the resultant conjugates were confirmed in adults and 4- to 7-year-old children. Succinylation of the carrier protein improved the immunogenicity of Shigella conjugates in mice and increased their yield. Based on these results, a clinical trial of O-SP conjugates of Shigella sonnei and Shigella flexneri 2a bound to succinylated mutant Pseudomonas aeruginosa exotoxin A (rEPAsucc) or native or succinylated Corynebacterium diphtheriae toxin mutant (CRM9 or CRM9succ) was conducted in healthy adults. The conjugates were safe and immunogenic. S. sonnei-CRM9, S. sonnei-CRM9succ, and S. sonnei-rEPAsucc elicited significant rises of geometric mean (GM) IgG anti-LPS within 1 week of injection (P < 0.001). At 26 weeks, the GM anti-LPS levels elicited by these three conjugates were similar and higher than their prevaccination levels (P < 0.0001). GM IgG anti-LPS levels elicited by S. flexneri 2a-rEPAsucc were significantly higher than those elicited by S. flexneri 2a-rCRM9succ at all intervals after injection. At 26 weeks, the levels of IgG anti-LPS in vaccinees were higher than their prevaccination levels (P < 0.0001). The serum antibody responses were specific, as there was no significant rise of anti-LPS to the heterologous O-SP in any vaccinee. Both conjugates elicited statistically significant rises of serum antibodies to the injected carrier protein. At 6 months, these five Shigella conjugates elicited higher fold rises than similar conjugates (D. N. Taylor et al., Infect. Immun. 61:3678-3687, 1993). Based on these data, we chose S. sonnei-CRM9 and S. flexneri 2a-rEPAsucc for evaluation in children.
authors.affiliation: Samuel Jared Pediatric Immunology Laboratory, Sheba Medical Center, Tel-Aviv, Israel. jpasswell@post.tau.ac.il
authors.forename: J H
authors.initials: JH
authors.lastname: Passwell
authors.forename: E
authors.initials: E
authors.lastname: Harlev
authors.forename: S
authors.initials: S
authors.lastname: Ashkenazi
authors.forename: C
authors.initials: C
authors.lastname: Chu
authors.forename: D
authors.initials: D
authors.lastname: Miron
authors.forename: R
authors.initials: R
authors.lastname: Ramon
authors.forename: N
authors.initials: N
authors.lastname: Farzan
authors.forename: J
authors.initials: J
authors.lastname: Shiloach
authors.forename: D A
authors.initials: DA
authors.lastname: Bryla
authors.forename: F
authors.initials: F
authors.lastname: Majadly
authors.forename: R
authors.initials: R
authors.lastname: Roberson
authors.forename: J B
authors.initials: JB
authors.lastname: Robbins
authors.forename: R
authors.initials: R
authors.lastname: Schneerson
mesh_terms: D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000276:immunology / Q000627:therapeutic use; D004405:Dysentery, Bacillary / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007557:Israel; D008297:Male; D019081:O Antigens / Q000627:therapeutic use*; D022281:Shigella Vaccines / Q000627:therapeutic use*; D018074:Vaccines, Conjugate / Q000627:therapeutic use*
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; C053395:CRM9 protein, bacteria; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D019081:O Antigens; D022281:Shigella Vaccines; D018074:Vaccines, Conjugate; C111749:pseudomonas exoprotein A protein, Pseudomonas aeruginosa