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Infect Immun, May 1998, p. 2186-2192, Vol. 66, No. 5
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Structural Properties of Group B Streptococcal Type III Polysaccharide Conjugate Vaccines That Influence Immunogenicity and Efficacy

Michael R. Wessels,1,2,* Lawrence C. Paoletti,1 Hilde-Kari Guttormsen,1 Francis Michon,3 Anello J. D'Ambra,3 and Dennis L. Kasper1

Channing Laboratory, Brigham and Women's Hospital,1 and Division of Infectious Diseases, Beth Israel Deaconess Medical Center,2 Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, and North American Vaccine, Inc., Beltsville, Maryland 207053

Received 11 December 1997/Returned for modification 29 January 1998/Accepted 18 February 1998

In this study, we tested the hypothesis that the immunogenicity and protective efficacy of polysaccharide-protein conjugate vaccines are influenced by three variables: (i) molecular size of the conjugate, (ii) molecular size of the polysaccharide used for conjugation, and (iii) extent of polysaccharide-to-protein cross-linking. Type III group B Streptococcus capsular polysaccharide was linked by reductive amination at multiple sites to tetanus toxoid to create a polysaccharide-protein conjugate (III-TT). A single lot of III-TT was fractionated into small, medium, and large Mr pools. Whereas all three conferred protection in a maternal immunization-neonatal challenge model in mice, the smallest Mr conjugate evoked less polysaccharide-specific immunoglobulin G (IgG) than the two larger Mr conjugates. To test whether the molecular size of the polysaccharide used for conjugation also affected the immunogenicity of the conjugate, vaccines were synthesized using capsular polysaccharides with Mrs of 38,000, 105,000, and 349,000. Polysaccharide-specific IgG responses in mice increased with the Mr of the polysaccharides, and protective efficacy was lower for the smallest polysaccharide conjugate compared to the other two vaccines. Immunogenicity testing of a series of vaccines prepared with different degrees of polysaccharide-to-protein cross-linking demonstrated higher polysaccharide-specific antibody responses as the extent of cross-linking increased. However, opsonic activity was greatest in mouse antiserum raised to a moderately cross-linked conjugate, suggesting that some antibodies evoked by highly cross-linked conjugates were directed to a nonprotective epitope. We conclude that conjugate size, polysaccharide size, and degree of polysaccharide-protein cross-linking influence the immunogenicity and protective efficacy of III-TT conjugate vaccines.

* Corresponding author. Mailing address: Channing Laboratory, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-0086. Fax: (617) 731-1541. E-mail: mwessels{at}channing.harvard.edu.

Infect Immun, May 1998, p. 2186-2192, Vol. 66, No. 5
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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