Rational chemical design of the carbohydrate in a glycoconjugate vaccine enhances IgM-to-IgG switching

doi:10.1073/pnas.0710799105

Rational chemical design of the carbohydrate in a glycoconjugate vaccine enhances IgM-to-IgG switching

*Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and
^§Institute for Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115;
^†New England Regional Primate Research Center, Southborough, MA 01772; and
^‡Institute for Biological Sciences, National Research Council of Canada, Ottawa, ON, Canada K1A 0R6

Edited by Rino Rappuoli, Novartis Vaccines, Siena, Italy, and approved February 1, 2008 (received for review November 14, 2007)

Abstract

Many pathogens are sheltered from host immunity by surface polysaccharides that would be ideal as vaccines except that they are too similar to host antigens to be immunogenic. The production of functional IgG is a desirable response to vaccines; because IgG is the only isotype that crosses the placenta, it is of particular importance in maternal vaccines against neonatal disease due to group B Streptococcus (GBS). Clinical studies found a substantially lower proportion of IgG—relative to IgM—among antibodies elicited by conjugates prepared with purified GBS type V capsular polysaccharide (CPS) than among those evoked by CPSs of other GBS serotypes. The epitope specificity of IgG elicited in humans by a conjugate prepared with type V CPS is for chemically desialylated type V CPS (dV CPS). We studied desialylation as a mechanism for enhancing the ability of type V CPS to induce IgM-to-IgG switching. Desialylation did not affect the structural conformation of type V CPS. Rhesus macaques, whose isotype responses to GBS conjugates match those of humans, produced functionally active IgG in response to a dV CPS–tetanus toxoid conjugate (dV-TT), and 98% of neonatal mice born to dams vaccinated with dV-TT survived lethal challenge with viable GBS. Targeted chemical engineering of a carbohydrate to create a molecule less like host self may be a rational approach for improving other glycoconjugates.

Footnotes

^¶To whom correspondence should be addressed. E-mail: dennis_kasper{at}hms.harvard.edu
This work was presented in part at the 93rd Annual Meeting of the American Association of Immunologists, May 12–16, 2006, Boston, MA.
Author contributions: D.L.K. designed research; H.-K.G., K.G.M., and W.J. performed research; H.-K.G., L.C.P., W.J., H.J.J., and D.L.K. analyzed data; and L.C.P., H.J.J., and D.L.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0710799105/DCSupplemental.