This was a phase IIb, open, randomised, controlled study conducted in two centres in the Philippines (Research Institute for Tropical Medicine and Phillippine General Hospital) and one centre in Saudi Arabia (King Abdulaziz Medical City in Riyadh). The study consisted of two phases: the vaccination phase (including the extended safety follow-up until Month 6) and the long-term persistence phase (up to five years after vaccination). At the time of the preparation of this manuscript, results up to the third year post-vaccination were available (covering the period December 2006 to August 2010).
Participants were randomised (3:1) into two parallel groups to receive either one dose of the MenACWY-TT vaccine (ACWY-TT group) or one dose of the MenACWY polysaccharide vaccine (Men-PS group) at Month 0. The randomisation list was generated at GlaxoSmithKline (Rixensart, Belgium) using a standard Statistical Analysis System (SAS®) program to number the vaccines. Treatment allocation at the investigator sites was performed using a central internet randomisation system. The randomisation algorithm used a minimisation procedure (block size of four) accounting for study centre and age of the subject (11–17 years and 18–55 years of age) in order to ensure a balanced distribution of the population in each group (2/3 of subjects were enrolled in the 11–17 year age stratum, and 1/3 of subjects were enrolled in the 18–55 year age stratum). The vaccines were administered in an open manner due to the differing appearance and route of administration of the study vaccines.
The study was conducted in accordance with the Good Clinical Practice Guidelines and the Declaration of Helsinki. The protocol and associated documents were reviewed and approved by local ethics committees (the Institutional Review Board from the National Guard Health Affair, Riyadh, Saudi Arabia and from the Research Institute for Tropical Medicine, Muntinlupa City, the University of the Philippines Manila Research Ethics Board (UPMREB), Manila, the Philippines). Written informed consent was obtained before enrolment from the participants aged at least 16 years in Saudi Arabia and 18 years in the Philippines. Written informed consent was obtained from the parents/guardians of younger participants, and a written informed assent was signed by these participants. In addition, consent was obtained if participants in the Philippines reached 18 years of age during the study. This study is registered at http://www.clinicaltrials.gov NCT00356369. A summary of the protocol is available at http://www.gsk-clinicalstudyregister.com (GSK study ID 107386).
The primary objectives of this study were to demonstrate non-inferiority of the MenACWY-TT vaccine over the MenACWY polysaccharide vaccine for the entire population in terms of vaccine response (measured by a serum bactericidal antibody assay using baby rabbit serum as exogenous complement source [rSBA]) and incidence of any grade 3 general symptom reported within four days after vaccination.
The secondary objectives of the study were to compare the immunogenicity and the persistence of the immune response of the MenACWY-TT vaccine with that of the MenACWY polysaccharide vaccine and to evaluate the reactogenicity and the safety of both vaccines.
Study participants were healthy adolescents and adults from the Philippines and Saudi Arabia aged 11 to 55 years at the time of vaccination, who had previously completed routine childhood vaccinations to the best of their, or their parents’/guardians’, knowledge.
Participants were excluded if they were immunosuppressed from any cause or were previously vaccinated with a meningococcal conjugate vaccine at any time or with a meningococcal polysaccharide vaccine against serogroup A, C, W-135, or Y within five years prior to the study. Participants with a history of meningococcal disease due to serogroup A, C, W-135, or Y; Guillain-Barré syndrome; any neurological disorders or seizures; allergic disease or reactions likely to be exacerbated by any component of the vaccine; or chronic alcohol consumption or drug abuse were also excluded. Moreover, participants were ineligible if they had used an investigational product within 30 days prior to the study, had received immunoglobulins or blood products in the preceding three months, or had a major congenital defect, serious illness, or acute disease at the time of enrolment. Females of childbearing potential were required to practice adequate contraception for 30 days prior to vaccination, have a negative pregnancy test at the time of vaccination, and continue contraceptive precautions for two months after vaccination.
One dose of the MenACWY-TT candidate vaccine (Nimenrix™, GlaxoSmithKline, Rixensart, Belgium) contained 5 μg of each of the meningococcal serogroups A, C, W-135, and Y polysaccharides individually conjugated to TT. A single MenACWY-TT vaccine dose was administered intramuscularly in the non-dominant deltoid of the participants in the ACWY-TT group. One dose of the MenACWY polysaccharide vaccine (Mencevax™ ACWY, GlaxoSmithKline, Rixensart, Belgium) contained 50 μg of each of the meningococcal serogroups A, C, W-135, and Y polysaccharides. A single MenACWY polysaccharide vaccine dose was administered subcutaneously in the non-dominant upper arm of the participants in the Men-PS group.
Blood samples were collected from all participants at Month 0, Month 1, Year 1, Year 2, and Year 3. Functional antibody responses against meningococcal serogroups A, C, W-135, and Y were assessed by rSBA . The target strains used in the rSBA assays were L10 for serogroup A, C11 for serogroup C, MP01240070 for serogroup W-135, and S-1975 for serogroup Y. rSBA titres ≥8 for serogroup C are considered to predict protection , and this threshold was extended to the other serogroups as well . rSBA titres ≥128, a more conservative correlate of protection, were also evaluated . Vaccine response was defined as an rSBA titre ≥32 at Month 1 in participants who were seronegative (rSBA titre <8) at pre-vaccination and as at least a four-fold increase in titre from Month 0 to Month 1 in participants who were seropositive at pre-vaccination.
In addition, antibody concentrations against TT were determined by enzyme-linked immunosorbent assay (ELISA) with an assay cut-off of 0.1 IU/mL . All assays were performed at GlaxoSmithKline’s central laboratory (Rixensart, Belgium), and laboratory personnel were blinded to the treatment group of the subject.
Safety and reactogenicity assessment
Local (pain, redness, and swelling) and general (fatigue, fever, gastrointestinal symptoms, and headache) solicited symptoms were recorded during four days and unsolicited adverse events (AEs) during one month after vaccination. The intensity of each symptom was graded on a three-level scale. Injection site redness and swelling were of grade 3 intensity if their diameter was >50 mm and fever if oral temperature was >39.5°C. All other symptoms of grade 3 intensity were defined as symptoms preventing normal activity.
New onset of chronic illnesses (NOCIs) and serious adverse events (SAEs) were recorded for up to six months post-vaccination. SAEs were defined as any medical event resulting in death, any life-threatening event, any event causing disability or requiring hospitalisation or prolongation of hospitalisation, or any congenital anomaly or birth defect in the offspring of a study participant. Moreover, SAEs related to vaccination and any events related to lack of vaccine efficacy were reported throughout the study. All solicited local reactions were considered causally related to vaccination. Causality of all other AEs was assessed by the investigators at the local study sites (independent from the Sponsor of the study).
With a target sample size of 460 participants evaluable for immunogenicity (345 in the ACWY-TT group and 115 in the Men-PS group), the global power to meet all the primary objectives of the study was at least 76%.
The total vaccinated cohort, on which the safety analyses were performed, included all vaccinated participants. The analyses of immunogenicity were performed on the according to protocol (ATP) immunogenicity cohort and on the ATP cohort for antibody persistence Year 1, Year 2, and Year 3, which included all evaluable study participants, who were vaccinated during the vaccination phase, meeting the eligibility criteria, with no elimination criteria during the study, and for whom data concerning immunogenicity endpoints were available for at least one tested antigen at Month 1, Year 1, Year 2, or Year 3, respectively.
The percentages of participants with antibody titres or concentrations above the proposed cut-offs and with a vaccine response as well as the geometric mean antibody titres (GMTs) or geometric mean antibody concentrations (GMCs) for the tested antigens were calculated with 95% confidence intervals (CIs) in each treatment group. The GMTs/GMCs were calculated by taking the anti-log of the mean of the log10 titre/concentration transformations. Antibody titres/concentrations below the cut-off of the assay were given an arbitrary value of half the cut-off for the purpose of GMTs/GMCs calculation.
Non-inferiority of the rSBA vaccine response induced by the MenACWY-TT vaccine over the MenACWY polysaccharide vaccine was demonstrated if the lower limit (LL) of the asymptotic standardised 95% CI for the difference between the ACWY-TT and the Men-PS groups in the percentage of participants with rSBA vaccine response was ≥ −12% for serogroups C, W-135, and Y and ≥ −15% for serogroup A (inferential analysis).
Potential statistically significant differences between groups were detected if the asymptotic standardised 95% CI for the difference in rates (percentages of participants with titres/concentrations above proposed cut-offs or with vaccine responses) between the two vaccine groups did not contain the value “0”, or if the 95% CI for the GMTs/GMCs ratios between groups did not contain the value “1” (exploratory analyses). The GMTs/GMCs ratios were computed by an analysis of covariance model on the log10 transformation of the titres/concentrations using the pre-vaccination log10 transformation of the titres/concentrations, the age strata, and the vaccine groups as covariates. No adjustment for multiplicity of secondary endpoints was made and significant results from the exploratory analyses should be interpreted with caution.
Non-inferiority of the MenACWY-TT vaccine over the MenACWY polysaccharide vaccine in terms of incidence of grade 3 general symptoms was demonstrated if the upper limit (UL) of the asymptotic 95% CI for the difference between the ACWY-TT and the Men-PS groups in the incidence of any grade 3 general symptom within four days after vaccination was below 5% (inferential analysis).
The percentages of participants reporting each solicited local and general symptom and each unsolicited AE were tabulated with exact 95% CIs. NOCIs, SAEs, and withdrawals due to AEs were described in detail.
The statistical analyses were performed using the SAS® software version 9.1 (SAS Institute Inc., Cary, NC, United States) and StatXact 7.0.