Retaining the structural integrity of disulfide bonds in diphtheria toxoid carrier protein is crucial for the effectiveness of glycoconjugate vaccine candidates

Filippo Carboni; Annabel Kitowski; Charlotte Sorieul; Daniele Veggi; Marta C. Marques; Davide Oldrini; Evita Balducci; Barbara Brogioni; Linda Del Bino; Alessio Corrado; Francesca Angiolini; Lucia Dello Iacono; Immaculada Margarit; Maria Rosaria Romano; Gonçalo J. L. Bernardes; Roberto Adamo

doi:10.1039/D1SC01928G

Retaining the structural integrity of disulfide bonds in diphtheria toxoid carrier protein is crucial for the effectiveness of glycoconjugate vaccine candidates†

Filippo Carboni,‡^a Annabel Kitowski,

‡^b Charlotte Sorieul,

^a Daniele Veggi,^a Marta C. Marques,^b Davide Oldrini,^a Evita Balducci,^a Barbara Brogioni,^a Linda Del Bino,^a Alessio Corrado,^a Francesca Angiolini,^a Lucia Dello Iacono,^a Immaculada Margarit,^a Maria Rosaria Romano,^a Gonçalo J. L. Bernardes

*^bc and Roberto Adamo

*^a

Author affiliations

* Corresponding authors

^a GSK, Via Fiorentina 10, 53100 Siena, Italy
E-mail: roberto.x.adamo@gsk.com

^b Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
E-mail: gbernardes@medicina.ulisboa.pt

^c Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
E-mail: gb453@cam.ac.uk

Abstract

The introduction of glycoconjugate vaccines marks an important point in the fight against various infectious diseases. The covalent conjugation of relevant polysaccharide antigens to immunogenic carrier proteins enables the induction of a long-lasting and robust IgG antibody response, which is not observed for pure polysaccharide vaccines. Although there has been remarkable progress in the development of glycoconjugate vaccines, many crucial parameters remain poorly understood. In particular, the influence of the conjugation site and strategy on the immunogenic properties of the final glycoconjugate vaccine is the focus of intense research. Here, we present a comparison of two cysteine selective conjugation strategies, elucidating the impact of both modifications on the structural integrity of the carrier protein, as well as on the immunogenic properties of the resulting glycoconjugate vaccine candidates. Our work suggests that conjugation chemistries impairing structurally relevant elements of the protein carrier, such as disulfide bonds, can have a dramatic effect on protein immunogenicity.

This article is part of the themed collection: Most popular 2022 organic chemistry articles

Chemical Science

Retaining the structural integrity of disulfide bonds in diphtheria toxoid carrier protein is crucial for the effectiveness of glycoconjugate vaccine candidates†

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Retaining the structural integrity of disulfide bonds in diphtheria toxoid carrier protein is crucial for the effectiveness of glycoconjugate vaccine candidates

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