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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 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.

* Corresponding author. Mailing address: Lea and Arie Pickel Chair in Pediatric Research, The Chaim Sheba Medical Center, Tel-Hashomer 5261, 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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