Investigating the immunodominance of carbohydrate antigens in a bivalent unimolecular glycoconjugate vaccine against serogroup A and C meningococcal disease

Abstract

Multicomponent constructs, obtained by coupling different glycans to the carrier protein, have been proposed as a way to co-deliver multiple surface carbohydrates targeting different strains of one pathogen and reduce the number of biomolecules in the formulation of multivalent vaccines. To assess the feasibility of this approach for anti-microbial vaccines and investigate the potential immunodominance of one carbohydrate antigen over the others in these constructs, we designed a bivalent unimolecular vaccine against serogroup A (MenA) and C (MenC) meningococci, with the two different oligomers conjugated to same molecule of carrier protein (CRM197). The immune response elicited in mice by the bivalent MenAC construct was compared with the ones induced by the monovalent MenA and MenC vaccines and their combinations. After the second dose, the bivalent construct induced good levels of anti-MenA and anti-MenC antibodies with respect to the controls. However, the murine sera from the MenAC construct exhibited good anti-MenC bactericidal activity, and very low anti-MenA functionality when compared to the monovalent controls. This result was explained with the diverse relative avidities against MenA and MenC polysaccharides, which were measured in the generated sera. The immunodominant effect of the MenC antigen was fully overcome following the third immunization, when sera endowed with higher avidity and excellent bactericidal activity against both MenA and MenC expressing strains were elicited. Construction of multicomponent glycoconjugate vaccines against microbial pathogens is a feasible approach, but particular attention should be devoted to study and overcome possible occurrence of immune interference among the carbohydrates.

Multicomponent polysaccharide–protein bioconjugation in the development of antibacterial glycoconjugate vaccine candidates

“…The concept has been recently extended to antibacterial multivalent vaccines including either multiple CPs 32 or a CP and an adjuvant 33 conjugated to a carrier. Nevertheless, such multivalent glycoconjugates have been prepared through the incorporation of each component in separate conjugation steps.…”

“…Nevertheless, such multivalent glycoconjugates have been prepared through the incorporation of each component in separate conjugation steps. 32 , 33 Herein we describe, for the first time, a multicomponent bioconjugation approach that enables the incorporation of two different polysaccharide antigens to a carrier protein in one pot, thus leading to a unique class of multivalent unimolecular glycoconjugate.…”

Comparative Dynamics of Monovalent and Bivalent Vaccination for Immunologically Unrelated Pathogens

“…However, the protection efficacy of such vaccines may not be as good as that provided by individually administered monovalent vaccines against different pathogens. A number of bivalent vaccines are currently being used in many countries, [5][6][7][8] however an important question is whether these vaccines could reduce the morbidity caused by different pathogens in the population without increasing vaccine doses compared to monovalent vaccines. To address this question, we developed, for the first time, epidemiological models for transmission dynamics of two immunologically unrelated pathogens, where immunity conferred by vaccination or natural infection of one pathogen does not provide any cross-protection against the other pathogen.…”

“…4 Since then, a number of multivalent combined or unimolecular vaccines have been produced to protect individuals against different pathogens or different serotypes of a pathogen using a single vaccine dose. [5][6][7] A particular example is the DTaP-IPV-Hib combined vaccine that protects individuals against diphtheria, tetanus, pertussis, polio and Hib. 8 Multivalent vaccines have the advantage of providing protection against two or more diseases in a single dose, and therefore eliminate a number of logistical and administrative challenges associated with vaccination using monovalent vaccines.…”

Simulating Immune Interference on the Effect of a Bivalent Glycoconjugate Vaccine againstHaemophilus influenzaeSerotypes “a” and “b”

“…We therefore developed a stochastic simulation model of humoral immune response to encapsulate the biological processes underlying T cell-dependent B cell activation and the antibody production. Using this model, we sought to evaluate the potential level of immune responses conferred by a bivalent combined (Hib-CP/Hia-CP) glycoconjugate vaccine and a bivalent unimolecular (Hib-CP-Hia) glycoconjugate vaccine [ 21 ], in the presence of preexisting immunity to serotype “b” of H. influenzae and CP.…”