In the Netherlands and Canada (Quebec), vaccination with a single dose of a monovalent conjugate vaccine against MenC given in the second year of life has resulted in a decrease of the incidence of diseases caused by this serogroup [14
]. However, protection against the other major meningococcal serogroups is also needed, especially for travellers to areas of high endemicity. Currently, two quadrivalent meningococcal conjugate vaccines have been licensed in Europe: the MenACWY-CRM197
vaccine for immunisation of children 2 years of age and older and the MenACWY-TT vaccine that extends protection to include toddlers in the second year of life, an age group at high risk for meningococcal disease. The present study was primarily designed to demonstrate the non-inferiority of MenACWY-TT versus MenC-CRM197
in terms of immune response to MenC in children 2–10 years of age. In addition, the immunogenicity to MenA, MenW-135 and MenY, and the safety profile of MenACWY-TT were assessed.
The primary objective of the study was met, and the immunogenicity of a single dose of MenACWY-TT was shown to be non-inferior to that of MenC-CRM197
in terms of rSBA-MenC vaccine response. However, exploratory analyses suggested that lower rSBA-MenC GMTs were measured after vaccination with MenACWY-TT compared with MenC-CRM197
. A similar finding was noted in a previous study conducted in infants showing that rSBA-MenC GMTs induced by the licensed MenACWY-CRM197
vaccine were lower than those induced by MenC-CRM197
]. These findings could be related to the differences in MenC capsular polysaccharide doses in MenACWY-TT or MenACWY-CRM197
(5 μg) as opposed to MenC-CRM197
(10 μg). Furthermore, the additional serogroups included in the quadrivalent vaccines compared to the monovalent vaccine may result in lower overall titres for MenC. Finally, it should be noted that, in contrast with MenACWY-TT and MenACWY-CRM197
contains an aluminium adjuvant.
Results of our study are in contrast with those of other trials in which MenACWY-TT was compared to another monovalent MenC-CRM197
vaccine (Meningitec™; Pfizer, formerly Wyeth) [32
]. In these trials, MenACWY-TT was shown to induce higher rSBA-MenC GMTs than the monovalent MenC-CRM197
vaccine in toddlers. This difference is consistent with results of other studies showing that the immune response induced by MenC-CRM197
(Menjugate™) was higher than that induced by the other monovalent MenC-CRM197
vaccine (Meningitec™) [44
The lower rSBA-MenC GMTs induced by MenACWY-TT compared to MenC-CRM197
in the present study are of unknown clinical significance, since >99 % of children had rSBA-MenC titres ≥1:128 at 1 month post-vaccination, suggesting that MenACWY-TT induced seroprotective antibody titres against MenC in the vast majority of the vaccine recipients. However, the lower rSBA-MenC GMTs may have an impact on antibody persistence and this is being explored in an ongoing extension study (NCT01266993). The persistence of antibodies in the serum is particularly important for preventing diseases that have a short incubation period, such as meningococcal diseases, for which the memory B-cell responses are not sufficiently rapid to prevent bacterial dissemination [3
]. The lower rSBA-MenC GMTs must be considered in light of the additional robust responses to MenA, MenW-135 and MenY induced by MenACWY-TT, which indicate broader serogroup coverage than that induced by the monovalent MenC conjugate vaccine.
Currently, there is no international consensus on whether rabbit (rSBA) or human (hSBA) complement source should be considered as standard for bactericidal activity measurements [21
]. Although the original correlate of protection was defined in terms of hSBA titres [20
], it was previously suggested that hSBA assays may have reduced sensitivity and that while hSBA titres ≥1:4 are predictive of protection, hSBA titres <1:4 may not necessarily predict susceptibility [8
]. Therefore, a functional assay using rabbit complement was used to evaluate the immunogenicity of the meningococcal vaccines in the present study. Moreover, three monovalent MenC vaccines were licensed in Europe based on rSBA-MenC responses, and during post-licensure surveillance, rSBA titres of 1:8 were confirmed as the antibody threshold that best correlated to vaccine effectiveness [1
The safety profile of MenACWY-TT observed in our study was in line with that observed in a previous study conducted in young children in Europe [32
]. However, solicited local symptoms seemed to be more frequently reported here than in another previous study conducted in children 2–10 years of age in the Philippines, India, Lebanon and Saudi Arabia [37
]. The differences between the safety profiles may reflect differences between the populations in which the vaccine was studied, both in terms of biological reactogenicity to the vaccine and cultural differences in AE reporting.
The present study was limited by its open design, which had the potential to bias the safety reporting by the investigators and parents/guardians. However, since it is most likely that bias would be in favour of the control monovalent vaccine versus the quadrivalent vaccine, the results of the safety comparison remain relevant. The study was also potentially limited by the lack of MenC-TT or quadrivalent meningococcal conjugate vaccines as control and the numerous exploratory statistical comparisons without multiplicity adjustment, which should be interpreted with caution.
The results of the present study suggest that MenACWY-TT has a clinically acceptable safety profile and the potential to offer protection against meningococcal disease to European children 2–10 years of age, since the vaccine was shown to provide protection against additional serogroups while maintaining protection against serogroup C.
Menactra is a trademark of Sanofi Pasteur.
Menveo and Menjugate are trademarks of Novartis Vaccines and Diagnostics, Inc.
Meningitec is a trademark of Pfizer, formerly Wyeth.
Nimenrix is a trademark of the GlaxoSmithKline Group of companies.