Immunogenicity of reduced dose priming schedules of serogroup C meningococcal conjugate vaccine followed by booster at 12 months in infants: open label randomised controlled trial

Abstract

Objective: To determine whether the immunogenicity of a single dose infant priming schedule of serogroup C meningococcal (MenC) conjugate vaccine is non-inferior to a two dose priming schedule when followed by a booster dose at age 12 months.

Design: Phase IV open label randomised controlled trial carried out from July 2010 until August 2013 SETTING: Four centres in the United Kingdom and one centre in Malta.

Participants: Healthy infants aged 6-12 weeks followed up until age 24 months.

Interventions: In the priming phase of the trial 509 infants were randomised in a 10:10:7:4 ratio into four groups to receive either a single MenC-cross reacting material 197 (CRM) dose at 3 months; two doses of MenC-CRM at 3 and 4 months; a single MenC-polysaccharide-tetanus toxoid (TT) dose at 3 months; or no MenC doses, respectively. Haemophilus influenzae type b (Hib)-MenC-TT vaccine was administered to all infants at 12 months of age. All infants also received the nationally routinely recommended vaccines. Blood samples were taken at age 5, 12, 13, and 24 months.

Main outcome measure: MenC serum bactericidal antibody assay with rabbit complement (rSBA) one month after the Hib-MenC-TT vaccine. Non-inferiority was met if the lower 95% confidence limit of the difference in the mean log10 MenC rSBA between the single dose MenC-CRM and the two dose MenC-CRM groups was >-0.35.

Results: The primary objective was met: after a Hib-MenC-TT booster dose at 12 months of age the MenC rSBA geometric mean titres induced in infants primed with a single MenC-CRM dose were not inferior to those induced in participants primed with two MenC-CRM doses in infancy (660 (95% confidence interval 498 to 876) v 295 (220 to 398)) with a corresponding difference in the mean log10 MenC rSBA of 0.35 (0.17 to 0.53) that showed superiority of the single over the two dose schedule). Exploration of differences between the priming schedules showed that one month after Hib-MenC-TT vaccination, MenC rSBA ≥ 1:8 was observed in >96% of participants previously primed with any of the MenC vaccine schedules in infancy and in 83% of those who were not vaccinated against MenC in infancy. The MenC rSBA geometric mean titres induced by the Hib-MenC-TT boost were significantly higher in children who were primed with one rather than two MenC-CRM doses in infancy. Only priming with MenC-TT, however, induced robust MenC bactericidal antibody after the Hib-MenC-TT booster that persisted until 24 months of age.

Conclusions: MenC vaccination programmes with two MenC infant priming doses could be reduced to a single priming dose without reducing post-boost antibody titres. When followed by a Hib-MenC-TT booster dose, infant priming with a single MenC-TT vaccine dose induces a more robust antibody response than one or two infant doses of MenC-CRM. Bactericidal antibody induced by a single Hib-MenC-TT conjugate vaccine dose at 12 months of age (that is, a toddler only schedule), without infant priming, is not well sustained at 24 months. Because of rapid waning of MenC antibody, programmes using toddler only schedules will still need to rely on herd protection to protect infants and young children.Trial registration Eudract No: 2009-016579-31; NCT01129518; study ID: 2008_06 (http://clinicaltrials.gov).

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: ALK, AmK, and DP have received travel grants from vaccine manufacturers to attend scientific meetings. AJP has previously conducted studies on behalf of Oxford University funded by vaccine manufacturers but does not receive any personal payments or travel support. AJP chairs the UK Department of Health’s (DH) Joint Committee on Vaccination and Immunisation (JCVI); the views expressed in this manuscript do not necessarily reflect the views of JCVI or DH. MDS, AF, SNF, and PH act as investigators for clinical trials conducted on behalf of their respective Universities and NHS Hospital Trusts sponsored by vaccine manufacturers and have participated in advisory boards but receive no personal payments from these activities. MDS and SNF have had travel and accommodation expenses paid by vaccine manufacturers to attend international conferences related to paediatric infectious disease. RB performs contract research on behalf of Public Health England for Baxter Bioscience, GlaxoSmithKline, Pfizer, Sanofi Pasteur, Sanofi Pasteur MSD, and Novartis Vaccines. PTH has conducted studies on behalf of St George’s University of London, funded by vaccine manufacturers but does not receive any personal payments or travel support. AmK and JM have received grants from the NIHR Oxford Biomedical Research Centre UK, GlaxoSmithKline Biologicals, and the European Society of Paediatric Infectious Diseases.

© Pace et al 2015.

Figures

Fig 1 MenC vaccination schedules and flow of infants in intention to treat population

Fig 2 Geometric mean titres (and 95% confidence interval) for meningococcal C (MenC) rabbit serum bactericidal antibody (rSBA) at visits performed at age 5, 12, 13, and 24 months according to type of MenC priming schedule (intention to treat population)