Serological and conformational properties of E. coli K92 capsular polysaccharide and its N-propionylated derivative both illustrate that induced antibody does not recognize extended epitopes of polysialic acid: Implications for a comprehensive conjugate vaccine against groups B and C N. meningitidis

Pon, Robert A; Khieu, Nam Huan; Yang, Qing-Ling; Brisson, Jean-Robert; Jennings, Harold J
August 2002
Canadian Journal of Chemistry;Aug2002, Vol. 80 Issue 8, p1055
Academic Journal
The capsular polysaccharide of E. coli K92 (K92P) contains elements in common with the capsular polysaccharides of both groups B and C N. meningitidis, and may therefore form the basis of a bivalent vaccine. In an attempt to augment the cross-protective immune response to group B meningococci, the N-acetyl groups of the K92P were replaced by N-propionyl groups (NPrK92P) and conjugated to protein. This strategy had previously been applied with success to the poorly immunogenic capsular polysaccharide of group B meningococcus (GBMP), and the bactericidal epitope was found to be exclusively mimicked by extended helical segments of the NPrGBMP. The NPrK92P-conjugate, in relation to a K92P-conjugate, failed to enhance the response to GBMP but did generate a measurable response to NPrGBMP, but only at the expense of a greatly reduced GCMP response. Despite the presence of an immune response to NPrGBMP, the anti-NPrK92 serum was not bactericidal. Competitive inhibition studies with NPrGBMP oligosaccharides suggested the NPrK92 antibodies could not cross-react with the protective epitope on group B meningococci, as defined by extended helical segments of the NPrGBMP, but only recognized short non-bactericidal NPrGBMP epitopes. This hypothesis was supported from the conformational and molecular dynamics studies of the K92P, which demonstrated a lack of extended conformations that resemble the GBMP extended epitope. Indeed, the conformational properties of the K92P more closely resembled those of the GCMP, thereby explaining the observed moderate cross-protection of the K92P antiserum towards group C meningococci. Thus, on the basis of these results, it can be concluded that K92P, regardless of N-propionyl modification, will not serve as an effective single vaccine component against both groups B and C meningococci.Key words: conjugate vaccine, Neisseria meningitidis, polysialic acid, NMR, molecular dynamics.Le polysaccharide capsulaire du E. coli K92 (K92P) comprend des éléments communs avec les polysaccharides capsulaires des N. meningitidis des groupes B et C et il pourrait donc être à la base d'un vaccin bivalent. Dans un essai d'augmenter la réponse immunitaire à protection croisée par rapport au méningocoque du groupe B, on a remplacé les groupes N-acétyles du K92P par des groupes N-propionyles (NPrK92P) et on les a conjugués à une protéine. On avait utilisé antérieurement cette stratégie avec succès avec le polysaccharide capsulaire peu immunogène du méningocoque du groupe B (GBMP) et on a trouvé que l'épitope bactéricide n'est répliqué que par des segments hélicoïdaux étendus du NPrGBMP. Par rapport à un conjugué à K92P, le conjugué au NPrK92P n'augmente pas la réponse au GBMP; il provoque toutefois une réponse mesurable au NPrGBMP, mais la réponse au GCMP est toutefois grandement réduite. Malgré la présence d'une réponse immunitaire au NPrGBMP, le sérum anti-NPrK92 n'est pas bactéricide. Des études d'inhibitions compétitives avec des oligosaccharides NPrGBMP suggèrent que les anticorps NPrK92 ne peuvent pas réagir de façon croisée avec l'épitope protecteur des méningocoques du groupe B, tels que définis par des segments hélicoïdaux étendus de NPrGBMP; ils ne reconnaissent que de courtes chaînes d'épitopes NPrGBMP non-bactéricides. Cette hypothèse est confirmée par des études de dynamiques moléculaire et conformationnelle du K92P qui ont démontré l'absence de conformations étendues qui pourraient ressembler à l'épitope étendu du GBMP. Les propriétés conformationnelles du K92P ressemblent en fait beaucoup plus à celles du GCMP; ceci expliquerait la protection croisée modérée observée du sérum K92P vis-à-vis des méningocoques du groupe C. Sur la base de ces résultats, on peut donc conclure que le K92P, même avec une modification N-propionyle, ne pourra pas servir de composant unique d'un vaccin efficace contre les méningocoques des groupes B et C.Mots clés : vaccin conjugué, Neisseria meningitidis, acide polysialique, RMN, dynamique moléculaire.[Traduit par la Rédaction]


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