ABSTRACT
The N19 polyepitope, consisting of a sequential string of universal human CD4(+)-T-cell epitopes, was tested as a carrier protein in a formulation of combined glycoconjugate vaccines containing the capsular polysaccharides (PSs) of Neisseria meningitidis serogroups A, C, W-135, and Y. Good antibody responses to all four polysaccharides were induced by one single immunization of mice with N19-based conjugates. Two immunizations with N19 conjugates elicited anti-MenACWY antibody titers comparable to those induced after three doses of glycoconjugates containing CRM197 as carrier protein. Compared to cross-reacting material (CRM)-based constructs, lower amounts of N19-MenACWY conjugates still induced high bactericidal titers to all four PSs. Moreover, N19-MenACWY-conjugated constructs induced faster and higher antibody avidity maturation against meningococcal C PS than CRM-based conjugates. Very importantly, N19-specific antibodies did not cross-react with the parent protein from which N19 epitopes were derived, e.g., tetanus toxoid and influenza virus hemagglutinin. Finally, T helper epitopes of the N19 carrier protein were effectively generated both in vivo (after immunization with the N19 itself) and in vitro (after restimulation of epitope-specific spleen cells). Taken together, these data show that the N19 polyepitope represents a strong and valid option for the generation of improved or new combined glycoconjugate vaccines.
Subject(s)
Bacterial Vaccines/immunology , Carrier Proteins/immunology , Epitopes, T-Lymphocyte/immunology , Epitopes/immunology , Glycoconjugates/immunology , Adjuvants, Immunologic/administration & dosage , Animals , Antibodies, Bacterial/biosynthesis , Antibody Affinity , Bacterial Infections/immunology , Bacterial Infections/prevention & control , Bacterial Proteins/administration & dosage , Bacterial Proteins/immunology , Bacterial Proteins/metabolism , Bacterial Vaccines/administration & dosage , Bacterial Vaccines/metabolism , Carrier Proteins/administration & dosage , Epitopes, T-Lymphocyte/administration & dosage , Epitopes, T-Lymphocyte/metabolism , Glycoconjugates/administration & dosage , Humans , Immunoglobulin G/biosynthesis , Mice , Neisseria meningitidis/immunology , Vaccines, Combined/administration & dosage , Vaccines, Combined/immunology , Vaccines, Conjugate/administration & dosage , Vaccines, Conjugate/immunologyABSTRACT
N19, a string of human universal CD4 T-cell epitopes from various pathogen-derived antigens, was shown to exert a stronger carrier effect than CRM197 for the induction of anti-group C Neisseria meningitidis capsular polysaccharide (MenC), after immunization of mice with various dosages of N19-MenC or CRM-MenC conjugate vaccines. After two immunizations, the N19-based construct induced anti-MenC antibody and protective bactericidal antibody titers higher than those induced by three doses of the CRM-MenC conjugate and required lower amounts of conjugate. N19-based conjugates are superior to CRM-based conjugates to induce protective immune responses to MenC conjugates.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , Meningococcal Vaccines/immunology , Neisseria meningitidis, Serogroup C/immunology , Recombinant Proteins/immunology , Vaccines, Conjugate/immunology , Amino Acid Sequence , Animals , Antibodies, Bacterial/blood , Bacterial Proteins/immunology , Diphtheria Toxin/immunology , Drug Carriers , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/metabolism , Female , Humans , Meningitis, Meningococcal/prevention & control , Meningococcal Vaccines/administration & dosage , Mice , Molecular Sequence Data , Recombinant Proteins/administration & dosage , Vaccines, Conjugate/administration & dosageABSTRACT
The immune system of the newborn is immature, and therefore it is difficult to induce protective immunity by vaccination in the neonatal period. Immunization of mothers during pregnancy against infections caused by encapsulated bacteria could thus be particularly attractive, as infants do not respond to polysaccharide (PS) antigens. Transmission of maternal vaccine-specific antibodies and protection of offspring against pneumococcal bacteremia and/or lung infection were studied in a neonatal murine model of pneumococcal immunization and infections. Adult female mice were immunized with native pneumococcal PS (PPS) of serotypes 1, 6B, and 19F or PPS conjugated to tetanus protein (Pnc-TT), and PPS-specific antibodies were measured in sera of mothers and their offspring. Effective transmission of maternal antibodies was observed, as PPS-specific immunoglobulin G levels in 3-week-old offspring of immunized mothers were 37 to 322% of maternal titers, and a significant correlation between maternal and offspring antibody levels was observed. The PPS-specific antibodies persisted for several weeks but slowly decreased over time. Offspring of Pnc-TT-immunized mothers were protected against pneumococcal infections with homologous serotypes, whereas PPS immunization of mothers did not protect their offspring, in agreement with the low titer of maternal PPS specific antibodies. When adult female mice were immunized with a meningococcal serogroup C conjugate vaccine (MenC-CRM), antibody response and transmission were similar to those observed for pneumococcal antibodies. Importantly, bactericidal activity was demonstrated in offspring of MenC-CRM-immunized mothers. These results demonstrate that this murine model of pneumococcal immunization and infections is suitable to study maternal immunization strategies for protection of offspring against encapsulated bacteria.
