Combined Conjugate Vaccines: Enhanced Immunogenicity with the N19 Polyepitope as a Carrier Protein

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.