An investigational tetravalent meningococcal serogroups A, C, W-135 and Y-tetanus toxoid conjugate vaccine co-administered with Infanrix™ hexa is immunogenic, with an acceptable safety profile in 12–23-month-old children

Abstract

Tetravalent meningococcal serogroups ACWY conjugate vaccines will provide an advantage to those at most risk of invasive meningococcal disease; namely young children. Co-administration of ACWY-TT with DTaP-HBV-IPV/Hib was assessed in a randomized trial in 793 children aged 12–23 months. Pre-specified criteria for non-inferiority of immunogenicity following co-administration versus separate ACWY-TT and DTaP-HBV-IPV/Hib administration were reached. One month post-vaccination, ≥97.3% of ACWY-TT vaccinees had rSBA titres ≥1:8 (all serogroups). Seroprotection/seropositivity rates against DTaP-HBV-IPV/Hib antigens were ≥98.2%. The safety profile of co-administration was similar to that of DTaP-HBV-IPV/Hib alone. ACWY-TT and DTaP-HBV-IPV/Hib co-administration during the second year would facilitate introduction of ACWY-TT into routine toddler vaccination schedules.

Introduction

Invasive meningococcal disease (IMD) is characterised by a fulminant clinical course, resulting in 10% mortality and high rates of permanent sequelae despite appropriate antibiotic and supportive therapy [1], [2]. Primary prevention by vaccination is therefore desirable to avoid the serious consequences of invasive infections.

The IMD disease burden is highest in children younger than 5 years of age [3], [4]. In European countries, serogroup B has the highest incidence in all age groups, followed in most countries by serogroup C [3], [5], [6]. Substantial declines in IMD due to serogroup C have been observed in those countries where routine meningococcal serogroup C conjugate vaccination programmes in infants and toddlers have been implemented [7], [8], [9] The percentage of IMD due to serogroups Y and W-135 ranges between 0% and 23% across Europe, being highest in Slovenia, Malta and Scandinavian countries [3]. Although, between 1999 and 2003, serogroup A was the second most common cause of IMD in Greece (19%) [10], few cases of serogroup A disease are currently reported in Europe [3].

The epidemiology of meningococcal disease is constantly evolving [5], [6]. Thus, although disease incidence due to serogroups A, Y and W-135 is lower than that of serogroups B and C in many parts of Europe, outbreaks due to these serogroups may occur as a result of strain evolution via capsular switching [11], or strain importation. The latter phenomenon was demonstrated in 2000 when, following a serogroup W-135 outbreak originating in Hajj pilgrims, cases were reported in nine European countries [12]. Increasing global travel activity also increases the risk of meningococcal strain importation into immunologically naive populations. Vaccination of young children with tetravalent conjugate vaccines targeting serogroups A, C, W-135 and Y would therefore provide a substantial advantage over monovalent serogroup C vaccines.

Tetravalent ACWY polysaccharide vaccines have been available for many years but protection is short-lived and efficacy is poor in children younger than 2 years of age in whom the disease burden is highest [13]. Two ACWY conjugate vaccines have more recently become available, but as their use is currently limited to individuals over 2 years of age [14], [15], effective multivalent conjugate vaccines for infants and toddlers are needed.

GlaxoSmithKline Biologicals’ (GSK) candidate ACWY conjugate vaccine, with all serogroups conjugated to the tetanus toxoid carrier protein (ACWY-TT), is being developed for use as a single dose as of 1 year of age. ACWY-TT has been previously shown to be immunogenic in toddlers 12–23 months of age [16], [17], [18]. Children frequently receive a booster dose of diphtheria–tetanus–acellular pertussis (DTaP)-based vaccines in their second year of life, and co-administration of ACWY-TT with these vaccines would facilitate its introduction into established vaccination schedules. The objective of the present study was to evaluate the co-administration of ACWY-TT with combined DTaP-hepatitis B-inactivated polio-Haemophilus influenzae type b conjugate vaccine (DTaP-HBV-IPV/Hib; Infanrix™ hexa, GSK), compared to each of the two vaccines given alone in healthy toddlers aged 12–23 months. The evaluation of the safety profile of co-administered ACWY-TT and DTaP-HBV-IPV/Hib is important since both vaccines contain tetanus toxoid (44 μg TT in ACWY-TT and 72 μg in DTaP-HBV-IPV/Hib). Since several European countries now routinely vaccinate against Neisseria meningitidis serogroup C, the acceptability of the replacement of monovalent MenC conjugate vaccines with ACWY-TT must be established, and therefore the immunogenicity of ACWY-TT in terms of MenC immune responses as compared to a licensed MenC conjugate vaccine was also evaluated in this study. Non-inferiority to licensed MenC conjugate vaccines has been evaluated in other studies [18], [19].