ReviewGlycoconjugate vaccines and immune interference: A review
Section snippets
Background
The development of polysaccharide–protein conjugate vaccines (CV) has been instrumental in preventing potentially fatal disease due to Haemophilus influenzae (Hib), Neisseria meningitidis and Streptococcus pneumoniae in infants and young children. It has become evident that as the number of glycoconjugates (valencies) and dosage of carrier protein (CP) included in CVs increase, so does the likelihood of interference with the immune response to conjugated and/or co-administered antigens.
Carrier-specific enhancement of T-cell help
Previously or simultaneously elicited T-cell responses to a CP may enhance responses to haptens conjugated to the same carrier (Fig. 1). For example, monovalent meningococcal serogroup C polysaccharide-Tetanus toxoid (MenC–TT) CVs enhanced the immunogenicity of Hib–TT given concomitantly in infants [2], [3], [4], [5], [6], [7], [8] and increases in anti-polyribosyl-ribitol-phosphate (PRP) geometric mean antibody concentrations (GMCs) were also observed when the combination of MenC–TT and Hib–TT
Hib conjugate vaccines
The Hib conjugates that have been used widely use TT or CRM197 as carrier at a poly(oligo)saccharide dosage of 10 μg and a protein:saccharide ratio of approximately 2 [35], [36], [37], [38]. A Hib–OMP (meningococcal outer-membrane–protein-complex consisting of a mixture of proteins) showed specific immunological behavior including early life responsiveness with substantial immune responses after a single dose but low boostability, which may relate to OMP intrinsic B-cell mitogenic and/or
TT and DT/CRM197-mediated interference within multivalent pneumococcal polysaccharide conjugate vaccines
Tetravalent pneumococcal TT and DT conjugates were found immunogenic in infants, albeit with strikingly different dose-ranges for TT and DT conjugates, with an increasing dose-range effect for 6B and 23F-DT conjugates and a decreased dose-range effect for the same serotypes conjugated to TT (Table 6) [73], [74]. These data are in line with findings for Hib and meningococcal TT and DT conjugates, whereby dose-dependent carrier antibody and carrier B-cell dominance may occur with TT, whereas DT
Co-administration-related interactions and bystander interference
Carrier-mediated interference may also impact immune responses when shared antigens are co-administered at distinct injection sites, since the mediators of interference (antibody-to-carrier; B-cell dominance; T-regulatory cells) are not site-dependent [74], [75].
With MenC–TT and DTPa–IPV–Hib–TT co-administration, and with Hib–MenC–TT and Hib–MenCY–TT combinations, an enhancement of Hib–TT antibody GMCs has been observed [2], [4], [5], [6], [7], [8], showing that co-administration or combination
Summary
The three most commonly used CPs (DT, CRM197 and TT), differ remarkably in their immunogenicity and ability to induce interference mechanisms. Strikingly, pre-existing immunity to TT leads clinically (adults) and pre-clinically (adult mice) to more easily demonstrable CIES as compared to DT [22], [25]. CRM197 conjugates require co-administration with DT [40], or priming with DT [42], [94] for optimal responses. DT conjugates in general appear less immunogenic as compared to TT and CRM197
Acknowledgements
The authors thank Dr. Joanne Wolter for assistance with preparation of the manuscript
Conflict of interest: Professor Dagan and Professor Siegrist have received honoraria unrelated to this work for participation to scientific advisory boards of various vaccine companies as well as research grants from pharmaceutical companies within the past 3 years. Dr. Poolman is an employee of GlaxoSmithKline Biologicals.
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