Subject demographics were similar in all groups (Table ). Of the 1,072 subjects enrolled, 1,054 completed the study in line with the protocol. Of the 18 subjects who did not complete the study, 9 withdrew their consent, 3 were lost to follow-up, 2 had study protocol violations, and 4 were defined as “unable to classify” (Fig. ).
Flowchart of subjects enrolled.
The subjects who did not complete the study consented, both when informed consent was given and when it was withdrawn, to the use of their partial data for the study.
Withdrawal of consent, follow-up drop-out, and protocol violations were due mainly to the difficulty in respecting examination times, especially when they coincided with summer holidays. In one case of protocol violation, the subject no longer fulfilled the recruitment requirements, because his situation had changed during the study. Finally, because of incomplete source data, four subjects could not be assigned with certainty to one or another of the three groups. The volunteers and their parents were aware that they could withdraw their consent at any time without having to provide any explanation; however, none of the parents and subjects who did offer an explanation, in response to a specific question, stated that withdrawal was due to the reactogenicity of the vaccination.
Safety and tolerability.
No clinically significant vaccine-related AEs were reported. Local reactions were reported by 50 to 80% of subjects across all three vaccine groups (Table ). The number of local reactions reported was highest at the injection site where Tdap was administered; while local reactogenicity rates at the MenACWY-CRM injection site were not affected by concomitant Tdap administration. The most frequently reported injection site reaction was pain; it was reported more frequently in the Tdap group (63 to 70%) than in the MenACWY-CRM group (23 to 32%) or the saline placebo group (12 to 16%) (Table ). Severe reactions were uncommon, whether the study vaccines were given concomitantly or with the saline placebo (<1 to 3% for MenACWY-CRM; 1 to 8% for Tdap) (Table ).
Solicited local and systemic reactions following vaccination with MenACWY-CRM administered concomitantly with Tdapa or with saline placebo
Systemic reactions were reported by 48% of the MenACWY-CRM-plus-saline placebo group, 55% of the MenACWY-CRM-plus-Tdap group, and 57% of the Tdap-plus-saline placebo group (Table ). Between 7% and 11% of subjects across all vaccine groups reported a systemic reaction that was rated as severe. The most commonly reported systemic reactions were headache (31 to 36%) and myalgia (22 to 36%). Severe headache was reported by 3 to 7% of all subjects and severe myalgia by 3 to 4% of all subjects (Table ).
Statistical analysis showed no significant differences between the frequency of adverse events scored as severe among subjects who received the combined vaccines and the frequency of the same AEs among the total of the subjects of the two groups receiving MenACWY-CRM or Tdap with saline placebo (for instance, chi-square values were 2.94 for pain [P, >0.05], 0.10 for chills [P, >0.05], 0.26 for nausea [P, >0.05], 1.07 for malaise [P, >0.04], 2.26 for myalgia [P, >0.05], 0.62 for arthralgia [P, >0.05], and 3.12 for headache [P, >0.05]).
While myalgia and arthralgia were monitored, fainting or changes in motor function were not specifically investigated. However, no subjects spontaneously reported any severe impairment of motor functions, whether vaccination was concomitant or separate.
In general, the proportions of subjects reporting any local or systemic reaction were higher among those who received Tdap plus saline placebo and among those who received MenACWY- CRM plus Tdap than among recipients of MenACWY-CRM plus saline placebo.
Immune responses to diphtheria, tetanus, and meningococcal serogroups A, C, W-135, and Y were similar, whether vaccine administration was separate or concomitant.
(i) Meningococcal serogroups A, C, W-135, and Y.
The proportions of subjects with an hSBA titer of ≥1:4 against all meningococcal serogroups were similar in the two MenACWY-CRM vaccine groups. For meningococcal serogroups C, W-135, and Y, values were in the 90 to 97% range; for serogroup A, they were in the 79 to 83% range (Fig. ). Geometric mean titers (GMTs) were also similar in the two MenACWY-CRM vaccine groups (Table ).
FIG. 2. Proportions of subjects achieving human serum bactericidal assay (hSBA) titers of ≥1:4 against Neisseria meningitidis serogroups A, C, W-135, and Y 1 month after vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM) plus (more ...)
Geometric mean titers and geometric mean concentrations of antibodies against vaccine antigens 1 month after vaccination
The proportion of subjects with seroprotective anti-diphtheria antibody concentrations (≥1.0 IU/ml) 1 month postvaccination was significantly higher when Tdap was administered concomitantly with MenACWY-CRM than when Tdap was administered with saline placebo (94% versus 85%; LL of 95% CI, >0%) (Fig. ) and was associated with higher geometric mean concentrations (GMCs) of anti-diphtheria antibodies (Table ).
FIG. 3. Proportions of subjects achieving antibody concentrations of ≥1.0 IU/ml against diphtheria and tetanus antigens 1 month after vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM) plus a combined tetanus, reduced diphtheria, (more ...) (iii) Tetanus.
One month postvaccination, 100% of subjects who had received concomitant MenACWY-CRM plus Tdap and 99% of those who had received Tdap plus saline placebo achieved a seroprotective anti-tetanus antibody concentration (≥1.0 IU/ml) (Fig. ). The anti-tetanus immune response to MenACWY-CRM plus Tdap was noninferior to the response to Tdap plus saline placebo (LL of 95% CI, −1%). Similarly, the GMCs of anti-tetanus antibodies in subjects receiving MenACWY plus Tdap were noninferior to those in subjects receiving Tdap plus saline placebo (12 versus 15 IU/ml, respectively; LL of 95% CI, 0.69) (Table ).
The proportion of subjects achieving a 4-fold increase in antibody concentrations against the pertussis antigens was lower for all three antigens when Tdap was administered concomitantly with MenACWY-CRM than when it was administered with saline placebo (Fig. ). Noninferiority was achieved for FHA, as demonstrated by the LL of the two-sided 95% CI (−9%) of the vaccine group difference, but not for the PRN or PT antigen (Table ). However, for PT the difference was slight (−14%) and not statistically significant, while for PRN the difference was moderate.
FIG. 4. Proportion of subjects achieving a 4-fold increase in concentrations of antibodies against pertussis antigens (pertussis toxoid [PT], filamentous hemagglutinin [FHA], and pertactin [PRN]) 1 month after vaccination with a quadrivalent meningococcal conjugate (more ...)
The reverse cumulative distribution curves, which show the distribution of the immune responses across the population of study subjects, are shown in Fig. .
FIG. 5. Reverse cumulative distribution of anti-pertussis toxoid (anti-PT) (A), anti-filamentous hemagglutinin (anti-FHA) (B), and anti-pertactin (anti-PRN) (C) titers prevaccination and 1 month postvaccination. MenACWY-CRM, quadrivalent meningococcal conjugate (more ...)