Safety and Immunogenicity of Improved Shigella O-Specific Polysaccharide-Protein Conjugate Vaccines in Adults in Israel

doi:10.1128/IAI.69.3.1351-1357.2001

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Infection and Immunity, March 2001, p. 1351-1357, Vol. 69, No. 3
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.3.1351-1357.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Safety and Immunogenicity of Improved Shigella O-Specific Polysaccharide-Protein Conjugate Vaccines in Adults in Israel

Justen H. Passwell,¹^,^* Efrat Harlev,¹ Shai Ashkenazi,² Chiayung Chu,³ Dan Miron,¹ Reut Ramon,¹ Naheed Farzan,¹ Joseph Shiloach,⁴ Dolores A. Bryla,³ Fathy Majadly,³ Robin Roberson,³ John B. Robbins,³ and Rachel Schneerson³

Samuel Jared Pediatric Immunology Laboratory, Sheba Medical Center,¹ and Schneider's Children's Hospital,² Tel-Aviv, Israel, and National Institute of Child Health and Human Development³ and National Institute of Diabetes and Digestive and Kidney Diseases,⁴ National Institutes of Health, Bethesda, Maryland 20892

Received 11 August 2000/Returned for modification 12 October 2000/Accepted 28 November 2000

Data suggest that the O-specific polysaccharide (O-SP) domain of the lipopolysaccharide (LPS) of Shigella species is bothan essential virulence factor and a protective antigen and thata critical level of serum immunoglobulin G (IgG) to this antigenwill confer immunity to shigellosis. Because covalent attachmentof polysaccharides to proteins increases their immunogenicity,especially in infants and in young children, the O-SP of Shigellaspecies were bound to medically useful proteins, and the safetyand immunogenicity of the resultant conjugates were confirmedin adults and 4- to 7-year-old children. Succinylation of thecarrier protein improved the immunogenicity of Shigella conjugatesin mice and increased their yield. Based on these results, a clinicaltrial of O-SP conjugates of Shigella sonnei and Shigella flexneri2a bound to succinylated mutant Pseudomonas aeruginosa exotoxinA (rEPA_succ) or native or succinylated Corynebacterium diphtheriaetoxin mutant (CRM9 or CRM9_succ) was conducted in healthy adults.The conjugates were safe and immunogenic. S. sonnei-CRM9, S. sonnei-CRM9_succ,and S. sonnei-rEPA_succ elicited significant rises of geometricmean (GM) IgG anti-LPS within 1 week of injection (P < 0.001).At 26 weeks, the GM anti-LPS levels elicited by these three conjugateswere similar and higher than their prevaccination levels (P <0.0001). GM IgG anti-LPS levels elicited by S. flexneri 2a-rEPA_succwere significantly higher than those elicited by S. flexneri 2a-rCRM9_succat all intervals after injection. At 26 weeks, the levels of IgGanti-LPS in vaccinees were higher than their prevaccination levels(P < 0.0001). The serum antibody responses were specific, as therewas no significant rise of anti-LPS to the heterologous O-SP inany vaccinee. Both conjugates elicited statistically significantrises of serum antibodies to the injected carrier protein. At6 months, these five Shigella conjugates elicited higher foldrises than similar conjugates (D. N. Taylor et al., Infect. Immun.61:3678-3687, 1993). Based on these data, we chose S. sonnei-CRM9and S. flexneri 2a-rEPA_succ for evaluation inchildren.

^* Corresponding author. Mailing address: Lea and Arie Pickel Chair in Pediatric Research, The Chaim Sheba Medical Center, Tel-Hashomer5261, Israel. Phone: 972 3530 2439. Fax: 972 3530 2562. E-mail:jpasswel{at}post.tau.ac.il.

Infection and Immunity, March 2001, p. 1351-1357, Vol. 69, No. 3
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.3.1351-1357.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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