Pediatric Infectious Disease Journal:
Phase II Study of a Three-dose Primary Vaccination Course of DTPa-IPV/Hib-MenC-TT Followed by a 12-month Hib-MenC-TT Booster in Healthy Infants
Khatami, Ameneh MB ChB*; Snape, Matthew D. MD, FRACP*; Ohene-Kena, Brigitte RSCN, BA*; Young, Katrina MB BS, DA†; Oeser, Clarissa MD‡; Michaelis, Louise J. MB ChB, MSc§¶; Macleod, Emma DipHE§¶; Smee, Heather DipHE‖; Van Der Meeren, Olivier MD††; Leyssen, Maarten MD††; Caubet, Magalie MA††; Yu, Ly-Mee MSc‡‡; Heath, Paul T. MB BS, FRCPCH‡; Faust, Saul N. PhD, MRCPCH§¶; Finn, Adam PhD, FRCPCH‖ **; Pollard, Andrew J. PhD, FRCPCH*
From the *Oxford Vaccine Group, NIHR Oxford Biomedical Research Centre and Department of Paediatrics, University of Oxford, Oxford; †St Mary’s Surgery, Cambridge; ‡St George’s Vaccine Institute, St Georges, University of London, London; §Faculty of Medicine, University of Southampton; ¶NIHR Wellcome Trust Clinical Research Facility, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton; ‖Bristol Children’s Vaccine Centre and NIHR Medicines for Children Research Network, South West, University Hospitals Bristol NHS Foundation Trust; **University of Bristol, Bristol, United Kingdom; ††GlaxoSmithKline Biologicals, Rixensart, Belgium; and ‡‡Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom.
Accepted for publication January 07, 2013.
This study was registered at ClinicalTrials.gov NCT00871338.
This study was sponsored by GlaxoSmithKline Biologicals, Belgium. The sponsor funded the study and developed the study protocol in collaboration with the investigators. Employees of the sponsor reviewed the article before submission for publication. A.J.P., A.F., M.D.S., P.T.H. and S.N.F. act as chief or principal investigators for clinical trials conducted on behalf of their respective NHS Trusts and/or Universities, sponsored by vaccine manufacturers, but receive no personal payments from them. A.J.P., A.F., M.D.S., P.T.H. and S.N.F. have participated in advisory boards for vaccine manufacturers, but receive no personal payments for this work. A.K., M.D.S., S.N.F. and P.T.H. have received financial assistance from vaccine manufacturers to attend conferences. All grants and honoraria are paid into accounts within the respective NHS Trusts or Universities, or to independent charities. O.V.D.M., M.L. and M.C. are employees of GSK Biologicals; O.V.D.M. and M.L. also own GSK stock options. The authors have no other funding or conflicts of interest to disclose.
Funding from the NIHR Biomedical Research Centre Programme through the Oxford Partnership Comprehensive Biomedical Research Centre provides support to the Oxford Vaccine Group, including salary support for A.K. and M.D.S. A.J.P. is a Jenner Investigator and James Martin Senior Fellow. A.K. has received funding from the James Martin Vaccine Design Institute (James Martin Fellowship). This study was in addition supported by the NIHR Southampton Wellcome Trust Clinical Research Facility, the NIHR Thames Valley, Hampshire and Isle of Wight, South London and Western Comprehensive Local Research Networks and the South West and London & South East NIHR Medicines for Children Local Research Networks. All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author).
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).
Address for correspondence: Ameneh Khatami, MB ChB, Churchill Hospital, Churchill Drive, Headington, Oxford, OX3 7LJ, United Kingdom. E-mail: email@example.com.
Aim: To test for immunologic noninferiority of antibody responses to Hib and MenC using a 6-in-1 combination vaccine (DTPa-IPV/Hib-MenC-TT) compared with DTPa-IPV-Hib plus MenC-CRM197, before and after a 12-month Hib-MenC-TT booster.
Methods: Pragmatic open-label, randomized, multicenter, UK study. “6-in-1” group received DTPa-IPV/Hib-MenC-TT at 2, 3 and 4 months; control group received DTPa-IPV-Hib at 2, 3 and 4 months and MenC-CRM197 at 3 and 4 months. Both groups received Hib-MenC-TT at 12 months. Concomitant vaccines: pneumococcal conjugate vaccine at 2, 4 and 13 months, and measles, mumps and rubella vaccine at 13 months.
Results: One hundred forty-two children were randomized to each group. One hundred children in the “6-in-1” group and 112 control group children completed the study according-to-protocol. One month postprimary immunizations: 100% of “6-in-1” group and 93.3% of control children had anti–polyribosylribitol phosphate (PRP) IgG ≥0.15 µg/mL; 96.2% and 100%, respectively, had rSBA-MenC titers ≥1:8. One month after booster all children met these thresholds, with anti-PRP geometric mean concentrations of 66.7 (53.3; 83.5) in “6-in-1” recipients and 26.9 (20.9; 34.6) in control children (4.4 [3.5; 5.4] and 3.0 [2.2–4.2] postprimary immunizations, respectively,). rSBA-MenC geometric mean titers were 3062.9 (2421.2; 3874.6) and 954.0 (761.3; 1195.5), respectively, postbooster and 393.2 (292.5; 528.7) and 3110.5 (2612; 3704.2) postprimary.
Conclusion: Noninferiority of DTPa-IPV/Hib-MenC-TT compared with DTPa-IPV/Hib plus MenC-CRM197 was demonstrated. In the “6-in-1” group, lower postprimary and greater postbooster rSBA-MenC geometric mean titers suggest memory B-cell priming may be favored by this vaccine over plasma cell induction. Furthermore, greater immunogenicity of TT conjugates used in both primary and booster vaccines in this group may be important.
Haemophilus influenzae type b (Hib) conjugate vaccines were introduced into the routine infant immunization schedule in the United Kingdom in 1992 and serogroup C meningococcal (MenC) conjugate vaccines in 1999. Both were accompanied by “catch-up” immunization campaigns, with subsequent rapid decline in rates of invasive disease attributed to these organisms. However, several studies have demonstrated waning of vaccine induced antibody1–5 and vaccine effectiveness beyond 1 year6–8 after immunization with MenC and Hib conjugate vaccines in early infancy. Consequently, a Hib-MenC tetanus toxoid (TT) conjugate booster (Hib-MenC-TT) was introduced in 2006 for all children aged 12 months.
Recent evidence suggests that the immune responses to both components of this booster vaccine are greater for infants who have received primary doses of Hib-MenC-TT concomitantly with a combination diphtheria, tetanus, acellular pertussis and poliovirus vaccine (DTPa-IPV), compared with children receiving primary immunizations with monovalent MenC CRM197-conjugate vaccine and combination DTPa-IPV-Hib.4,9 This difference persists until at least 5 years of age.10 Combining Hib-MenC-TT and DTPa-IPV for use in infancy as a single vaccine could therefore more effectively prime infants to respond to the Hib-MenC-TT booster than the current UK immunization schedule, while using fewer injections. We studied the immunogenicity and tolerability of a combined DTPa-IPV-Hib-MenC-TT vaccine when administered to healthy infants in the United Kingdom at 2, 3 and 4 months of age, followed by a 12-month booster dose of Hib-MenC-TT.
Study Design and Setting
We conducted a pragmatic open-label, randomized, multicentre trial in 5 centers in the United Kingdom (Oxford, Bristol, Southampton, London and Cambridge). Ethical approval was obtained from Oxfordshire Research Ethics Committee C (OxREC 09/H0606/24).
Participants and Vaccines
Children were randomized 1:1 either to receive 3 doses of a “6-in-1” combination DTPa-IPV/Hib-MenC-TT vaccine (GlaxoSmithKline Biologicals, Rixensart, Belgium) at 2, 3 and 4 months of age, with 2 doses of a 7-valent pneumococcal conjugate vaccine (PCV-7; Prevenar, Wyeth, Pearl River, NY) at 2 and 4 months of age (“6-in-1” group), or to receive immunizations according to the UK immunization schedule at the time: DTPa-IPV-Hib vaccine (Pediacel, Sanofi-Pasteur MSD, Lyon, France) at 2, 3 and 4 months of age, PCV-7 at 2 and 4 months of age and MenC-CRM197 (Menjugate, Novartis Vaccines and Diagnostics) at 3 and 4 months of age (control group). The 6-in-1 vaccine was produced by mixing DTPa-IPV (Infanrix-IPV, GSK Biologicals) and Hib-MenC-TT (Menitorix, GSK Biologicals) vaccines in a syringe immediately before administration.
Both groups received a Hib-MenC-TT booster at 12 months of age. All children were offered a booster dose of a 13-valent pneumococcal conjugate vaccine (PCV-13; Prevenar-13, Wyeth) and a measles, mumps and rubella vaccine (Priorix, GSK Biologicals) at 13 months of age (PCV-13 replaced PCV-7 in the UK immunization schedule in April 2010). These vaccines were provided as part of the routine immunization schedule and were not associated with study endpoints. Figure 1 outlines study vaccines and procedures.
Eligible participants were healthy infants aged 6 to 12 weeks at the time of first vaccination, born at 36 to 42 weeks gestation, for whom written informed consent was obtained from the parent/legal guardian. Specific exclusion criteria are listed in Table (Supplemental Digital Content 1, http://links.lww.com/INF/B458). Vaccination was delayed for any moderate to severe illness or intercurrent febrile illness with axillary temperature ≥37.5°C.
Five microliter blood samples were drawn before and approximately 1 month after the third primary vaccination dose (at 4 and 5 months of age, respectively) and again before and approximately 1 month after the Hib-MenC-TT booster (at 12 and 13 months). Solicited local and general symptoms occurring within 8 days after each vaccination were recorded in diary cards, as well as any other adverse events (AEs) occurring within 31 days after each vaccination. Information on serious AEs occurring at any time-point were also collected.
Serum concentrations of IgG against Hib (anti-PRP), diphtheria (anti-D), tetanus (anti-T) and pertussis antigens (pertactin [PRN], filamentous haemagglutinin [FHA] and pertussis toxin [PT]) were measured by enzyme-linked immunosorbent assay. Serotype-specific antipneumococcal IgG levels were measured by 22F-inhibition enzyme-linked immunosorbent assay.11 Anti-PRP concentrations ≥0.15 µg/mL and ≥1 µg/mL were used as correlates of protection against Hib disease.12,13 The assay threshold for antipneumococcal IgG was >0.20 μg/mL, >0.1 IU/mL for anti-D and anti-T IgG and >5 EL U/mL for IgG specific to pertussis antigens.
Functional anti-MenC activity was determined by serum bactericidal assay using baby rabbit complement (rSBA-MenC). Titers were expressed as the reciprocal of the dilution resulting in 50% inhibition, and ≥1:8 and ≥1:128 were used as correlates of protection.6,14,15 Results for the humoral immune response to polio serotypes 1, 2 and 3 are not presented in the present article because they were not validated at the time of submission. All assays were performed at the laboratories of GSK Biologicals (Rixensart). Laboratory personnel were blinded for group allocation.
Analysis of Immunogenicity
Analysis of immunogenicity was based on children who completed all study procedures according-to-protocol (ATP). Coprimary objectives were to demonstrate immunologic noninferiority at 5 months of age for antibody against Hib and MenC for children receiving the combination vaccine (DTPa-IPV/Hib-MenC-TT) compared with children receiving separate DTPa-IPV-Hib and MenC-CRM197 vaccines. Secondary objectives included demonstration of noninferiority of immune response to diphtheria and tetanus at 5 months of age, persistence of immune response to all antigens at 12 months of age and response to the Hib-MenC-TT booster measured at 13 months of age. Comparisons of immune responses to the pneumococcal serotypes at 5 months of age were exploratory.
The percentages of children achieving the response threshold for each antigen, along with exact 95% confidence intervals (CIs), were calculated.16 Standardized asymptotic CIs for the difference between groups (control minus “6-in-1”) in the percentage of children achieving each threshold were calculated,17 and noninferiority was demonstrated if the upper limit of the 95% CI was ≤10%. A statistically significant difference was inferred if the 95% CI for the differences between groups in terms of percentage of children achieving each threshold excluded 0%. Geometric mean concentrations or geometric mean titers (GMCs or GMTs) for antibody against each antigen were also calculated with 95% CIs. Results below the threshold for detection were given a value of half of the threshold for these calculations. A statistically significant difference in GMCs or GMTs was inferred if the 95% CI for the ratio between groups (control/“6-in-1”) calculated using an analysis of variance model on the log10 transformation of the concentrations or titers excluded 1.
Analysis of Safety
Safety analysis was performed on the total vaccinated cohort. Incidence rates of all solicited and unsolicited, local and general AEs occurring within 4 or 8 days after each dose of vaccine were calculated according to the type of symptom, severity (any or grade 3) and relationship to vaccination. Incidence rates of unsolicited AEs reported within 31 days after vaccination were summarized. Rates of antipyretic and concomitant medication use during the 8 and 31 days after vaccination were calculated. Serious AEs and withdrawals due to AEs were described in detail. Ninety-five percent CI for the difference between groups and 2-sided P values were calculated and P values <0.05 were considered statistically significant.
Power to conclude noninferiority for all vaccine antigens was estimated to be >80% with at least 126 participants per group in the ATP cohort, based on results from the UK participants in a study using separate but concomitant DTaP-IPV and Hib-MenC-TT vaccines at 2, 3 and 4 months of age.18 The target sample size was calculated as 140 participants per group, assuming a 10% dropout.
Two hundred eighty-four infants were enrolled between June and December 2009; 142 infants were randomly assigned to each study group. Mean age at enrolment was 8 weeks (range 6 to 11 weeks), and baseline characteristics were similar between groups, although there were slightly more female infants in the control group (58.6% versus 41.4% at enrolment). 88.5% of participants were Caucasian, and mean weight was 4.9 kg (range 3 to 8 kg). The median age at booster vaccination was 12 months (range 11 to 13 months). Figure 2 shows the number of participants included in the analyses for immunogenicity (ATP cohorts) and safety (total vaccinated cohorts) endpoints.
One month after completion of primary immunizations, the combination vaccine was noninferior to DTPa-IPV-Hib in terms of the percentage of participants achieving the response threshold for Hib (anti-PRP ≥0.15 µg/mL in 93.3% of control children, 100% of the “6-in-1” group, difference between groups [95% CI]: –6.72% [–12.72%; –3.16%]) and MenC (100% and 96.2%, respectively, with rSBA-MenC titer ≥1:8, difference between groups: 3.81% [0.44%; 9.41%]). Persistence of antibodies against both antigens was similar between groups before the Hib-MenC-TT booster. All children achieved anti-PRP concentrations ≥1 µg/mL by 13 months of age, although postbooster anti-PRP IgG GMC were higher in the “6-in-1” group (GMC ratio 0.40 [0.29; 0.57]). Despite achieving lower rSBA-MenC GMTs after primary immunizations, children in the “6-in-1” group made a greater booster response to Hib-MenC-TT compared with children in the control group (postbooster GMT ratio: 0.31 [0.23; 0.43]). The immunogenicity results for Hib and MenC at all time-points are shown in Figures 3 and 4 as well as Fig., Supplemental Digital Content 2, http://links.lww.com/INF/B459. Noninferiority was also demonstrated with respect to the percentage of participants achieving the response threshold for Hib and MenC at 13 months of age, despite a smaller number of participants within the ATP cohort for immunogenicity at the booster stage of the study (anti-PRP ≥0.15 µg/mL in 100% of each group, difference between groups: 0.0% [–3.42%; 3.99%], rSBA-MenC titer ≥1:8, difference between groups: 0.0% [–3.33%; 3.79%]).
The combination vaccine was also noninferior with respect to the percentage of participants who met the response thresholds for antibody against diphtheria and tetanus 1 month after primary immunizations. Exploratory analysis also demonstrated that the percentage of participants with serotype-specific antipneumococcal antibody concentrations ≥0.2 μg/mL was similar between groups at 5 months with the exception of serotype 23F (94.2% in controls compared with 78.7% in the “6-in-1” group, IgG GMCs 0.89 compared with 0.58, respectively). Table 1 lists the immunogenicity results for diphtheria, tetanus, pertussis and pneumococcal antigens at 5 months of age, and Table, Supplemental Digital Content 3, http://links.lww.com/INF/B460, shows the persistence of antibody against diphtheria, tetanus and pertussis to 12 months of age. Statistically significant differences between groups should be interpreted with caution as no adjustments were made for multiple comparisons.
The combination vaccine was well tolerated overall. Figure5 represents a summary of reactogenicity results after primary and booster immunizations. Two serious AEs possibly related to study vaccines occurred: 1 inguinal lymph node abscess (control group) after DTPa-IPV-Hib and PCV-7 immunization at 2 months of age, and an episode of transient arthritis (“6-in-1” group) after Hib-MenC-TT immunization at 12 months. There were no statistically significant differences between study groups in the rates of local or general symptoms occurring in the 8 and 31 days after vaccinations in the primary schedule or in the rates of concomitant medication use. In 8 days after booster vaccination, more children reported local symptoms in the “6-in-1” group compared with the control group (63.3% versus 45.9%); however, there were no statistical differences in the rates of grade 3 symptoms or symptoms requiring medical advice. There were no significant differences between groups in the rates of general symptoms or concomitant medication use in the 8 and 31 days after booster vaccination. The majority of local symptoms reported after vaccinations occurred in the first 4 days of follow-up. Thirty-six percent the 6-in-1 group and 33.3% of control children received any antipyretic medication within 8 days after the booster vaccine.
This study reports the immunogenicity and tolerability of a novel combination DTPa-IPV/Hib-MenC-TT vaccine administered to infants at 2, 3 and 4 months of age, as part of the UK childhood immunization schedule. It demonstrates noninferiority 1 month after the primary immunizations, at 5 months of age, of the combination vaccine in the percentage of children meeting the assay thresholds for immune response against each of the antigens tested, compared with children receiving routine immunizations with DTPa-IPV/Hib and MenC-CRM197. More importantly, children receiving the combination vaccine in their primary schedule achieved higher anti-PRP GMCs and rSBA-MenC GMTs compared with control children after the Hib-MenC-TT booster vaccine at 12 months of age.
These data are in line with a previous study comparing separate but concomitant DTPa-IPV and Hib-MenC-TT vaccination with DTPa-IPV plus another MenC-CRM197 vaccine9 (Meningitec Pfizer) when both schedules were administered at 2, 3 and 4 months of age. This study, conducted in the United Kingdom and Poland, also demonstrated greater responses to the Hib-MenC-TT booster in children receiving primary doses of Hib-MenC-TT. These findings may in part be due to use of the same Hib-MenC-TT vaccine for both priming and boosting, which may contribute to a greater booster response with respect to both anti-PRP concentrations and rSBA-MenC titers. However, higher anti-PRP levels have also been seen in infants boosted with a combination DTaP-Hepatitis B (HepB)-IPV/Hib vaccine when primed with Hib-MenC-TT and DTaP-HepB-IPV compared with infants who had received primary doses of either MenC-CRM197 or MenC-TT and DTaP-HepB-IPV/Hib.19 Furthermore, separation of the Hib component from a combination vaccine containing acellular pertussis antigens has been shown to improve the anti-PRP immune response.20
Several compositional differences between the vaccines administered to the 2 study groups may have an effect on the observed immunogenicity results. MenC-CRM197 contains 10 µg of the C11 strain of MenC polysaccharide, conjugated to 12.5–25.0 µg of CRM197, and 1 mg of aluminium hydroxide adjuvant. Hib-MenC-TT contains 5 µg of PRP polysaccharide conjugated to 12.5 µg of TT, 5 µg of MenC polysaccharide (C11 strain) conjugated to 5 µg of TT, and is nonadjuvanted. The effect of different carrier proteins on the immune response to conjugate vaccines is unclear. The use of TT carrier proteins for both priming and boosting may be important as TT conjugate vaccines induce a greater immune response than CRM197-conjugate vaccines, with better persistence of functional antibody, which has been demonstrated for both Hib-MenC-TT4 and MenC-TT vaccines.21–24 Prior immunization with TT vaccine alone reduced the immune response to MenC-TT whereas prior immunization with a diphtheria vaccine did not affect the response to MenC-CRM197 vaccine.24 In addition, concomitant immunization of infants with a TT-conjugated pneumococcal vaccine has been reported to result in lower anti-PRP responses after primary immunization with a Hib-TT containing vaccine.25 Conversely, anti-PRP responses to primary Hib-TT containing vaccines were enhanced by coadministration of MenC-TT compared with MenC-CRM197 vaccines.21,26,27 Anti-PRP concentrations were also higher when a Hib-CRM197 vaccine was used in the same schedule as a MenC-CRM197 vaccine compared with a HepB control vaccine.28
A carrier dose-related effect has been demonstrated in a recent meta-analysis, which found that with total CRM197 dose of approximately 50 µg a trend toward lower MenC SBA GMTs was observed after coadministration of MenC-CRM197 and other CRM197-based conjugate vaccines.29 In contrast, no such dose-related effect has been clearly identified with respect to the total TT dose and anti-PRP response to Hib-TT.30 Thus inhibitory or enhancing effects from different carrier proteins may be due to a combination of factors including timing of coadministered vaccines, the total dose of the various antigens and carrier proteins and also the specific characteristics of the polysaccharide.
In the “6-in-1” group in our study, lower rSBA-MenC GMTs after primary immunizations but greater postbooster rSBA-MenC GMTs suggest that priming of memory B-cells is favored by the combination vaccine at the expense of plasma cell induction, providing potential for a strong response upon reexposure. The rSBA-MenC GMTs were significantly lower in the “6-in-1” group after 3 doses of the combination vaccine at 2, 3 and 4 months of age compared with those after 2 doses of MenC-CRM197 at 3 and 4 months of age. However, lower postprimary rSBA titers in this group may also be partly due to interference from other antigens contained in the combination vaccine, when compared with the immune response to a monovalent MenC conjugate vaccine.
These findings are also in line with previous evidence that after primary immunizations with monovalent MenC conjugate vaccine, rSBA-MenC GMTs were higher than in children primed with Hib-MenC-TT.19 In this previous study, MenC-CRM197 recipients had higher postprimary rSBA-GMTs compared with Hib-MenC-TT recipients. It is not possible to compare booster responses in these children who received a polysaccharide vaccine at 1 year of age rather than a conjugate vaccine booster. This effect is also evident in slightly older children with a trend toward lower (although not statistically different) rSBA-MenC GMTs in MenC-naive children given a dose of Hib-MenC-TT at a year of age compared with those given separate Hib-TT and MenC-CRM197 vaccines. One year after vaccination, children in the Hib-MenC-TT group had higher rSBA-MenC titers.31
Although protein conjugate vaccines have been shown to induce memory B-cells,32,33 this anamnestic response may be too slow to limit disease34–36 on subsequent exposure. Thus, although immune memory may contribute to immunity, ongoing protection at an individual level against these encapsulated organisms is thought to rely critically on sustained serum antibody levels.37 For Hib and MenC, the height of the antibody response to the Hib-MenC-TT booster at 12 months of age correlates with the persistence of antibody through early childhood.4,10 Consequently, there is an advantage to primary immunization schedules that result in a greater response to the Hib-MenC-TT booster.
The “6-in-1” vaccine was shown to be well tolerated with few grade 3 symptoms or symptoms requiring a medical visit (data not shown). Higher rates of local side effects were reported after Hib-MenC-TT booster vaccination in children who had received primary doses of the combination vaccine; however, the majority of these were mild, with only a few grade 3 symptoms (2.2% [0.4%–6.2%]). Combination vaccines afford protection against more diseases with fewer injections, which may potentially increase acceptability to parents, as well as allowing space within an already crowded immunization schedule for the introduction of newly developed vaccines. However, an inherent disadvantage of combination vaccines is their lack of flexibility in terms of the number of doses of each antigen (in this case, MenC) that can be administered throughout the schedule. Although the results of this study would not be generalizable to schedules where HepB vaccine is routinely administered in infancy (usually in a combined DTaP-HepB-IPV/Hib formulation), interference between concomitant and combination vaccine components and the differential response to primary and booster vaccines are important concepts to consider when designing or improving national immunization schedules.
Our study demonstrated noninferiority of a combination DTPa-IPV/Hib-MenC-TT vaccine compared with DTPa-IPV-Hib-TT plus MenC-CRM197 with respect to the immune response to Hib, MenC and coadministered antigens 1 month after the primary course of immunizations. In the “6-in-1” group, the lower rSBA-MenC GMTs after primary immunizations and greater GMTs after a 12-month Hib-MenC-TT booster suggest that priming of memory B-cells is favored by the combination vaccine at the expense of plasma cell induction, providing potential for a strong response upon reexposure. Furthermore, greater immunogenicity of TT conjugates used in both primary and booster vaccines in this group may be important.
We acknowledge the contributions of the staff members and nurses who were involved in this study. We also thank the participants of this study and their family members. In addition, we thank Kay Bhatowa for study coordination, Valérie Haezebroeck for the serological analysis, Anne Sumbul and Lisa Allamassey for the statistical analysis and Garima Pallavi, Prapti Bose and Bhakthi Pereira for clinical report writing (Kay Bhatowa, Garima Pallavi, Prapti Bose, Bhakthi Pereira and Anne Sumbul are employees of GlaxoSmithKline Biologicals; Lisa Allamassey is an employee of Alten).
1. Trotter CL, McVernon J, Andrews NJ, et al. Antibody to Haemophilus influenzae
type b after routine and catch-up vaccination. Lancet. 2003;361:1523–1524
2. Heath PT, Booy R, Azzopardi HJ, et al. Antibody concentration and clinical protection after Hib conjugate vaccination in the United Kingdom. JAMA. 2000;284:2334–2340
3. Campbell H, Borrow R, Salisbury D, et al. Meningococcal C conjugate vaccine: the experience in England and Wales. Vaccine. 2009;27(suppl 2):B20–B29
4. Khatami A, Snape MD, John T, et al. Persistence of immunity following a booster dose of Haemophilus influenzae
type B-Meningococcal serogroup C glycoconjugate vaccine: follow-up of a randomized controlled trial. Pediatr Infect Dis J. 2011;30:197–202
5. Khatami A, Peters A, Robinson H, et al. Maintenance of immune response throughout childhood following serogroup C meningococcal conjugate vaccination in early childhood. Clin Vaccine Immunol. 2011;18:2038–2042
6. Campbell H, Andrews N, Borrow R, et al. Updated postlicensure surveillance of the meningococcal C conjugate vaccine in England and Wales: effectiveness, validation of serological correlates of protection, and modeling predictions of the duration of herd immunity. Clin Vaccine Immunol. 2010;17:840–847
7. Trotter CL, Andrews NJ, Kaczmarski EB, et al. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet. 2004;364:365–367
8. Ramsay ME, McVernon J, Andrews NJ, et al. Estimating Haemophilus influenzae
type b vaccine effectiveness in England and Wales by use of the screening method. J Infect Dis. 2003;188:481–485
9. Pace D, Snape M, Westcar S, et al. A novel combined Hib-MenC-TT glycoconjugate vaccine as a booster dose for toddlers: a phase 3 open randomised controlled trial. Arch Dis Child. 2008;93:963–970
10. Khatami A, Snape MD, Wysocki J, et al. Persistence of antibody response following a booster dose of Hib-MenC-TT glycoconjugate vaccine to five years: a follow-up study. Pediatr Infect Dis J. 2012;31:1069–1073
11. Concepcion NF, Frasch CE. Pneumococcal type 22f polysaccharide absorption improves the specificity of a pneumococcal-polysaccharide enzyme-linked immunosorbent assay. Clin Diagn Lab Immunol. 2001;8:266–272
12. Eskola J, Käyhty H, Peltola H, et al. Antibody levels achieved in infants by course of Haemophilus influenzae
type B polysaccharide/diphtheria toxoid conjugate vaccine. Lancet. 1985;1:1184–1186
13. Anderson P. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae
type b. J Infect Dis. 1984;149:1034–1035
14. Andrews N, Borrow R, Miller E. Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England. Clin Diagn Lab Immunol. 2003;10:780–786
15. Borrow R, Balmer P, Miller E. Meningococcal surrogates of protection–serum bactericidal antibody activity. Vaccine. 2005;23:2222–2227
16. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika. 1934;26:404–413
17. Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med. 1998;17:873–890
18. Pace D, Snape M, Westcar S, et al. A new combination Haemophilus influenzae
type B and Neisseria meningitidis
serogroup C-tetanus toxoid conjugate vaccine for primary immunization of infants. Pediatr Infect Dis J. 2007;26:1057–1059
19. Schmitt HJ, Maechler G, Habermehl P, et al. Immunogenicity, reactogenicity, and immune memory after primary vaccination with a novel Haemophilus influenzae-Neisseria meningitidis
serogroup C conjugate vaccine. Clin Vaccine Immunol. 2007;14:426–434
20. Eskola J, Ward J, Dagan R, et al. Combined vaccination of Haemophilus influenzae
type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis. Lancet. 1999;354:2063–2068
21. Richmond P, Borrow R, Goldblatt D, et al. Ability of 3 different meningococcal C conjugate vaccines to induce immunologic memory after a single dose in UK toddlers. J Infect Dis. 2001;183:160–163
22. Borrow R, Andrews N, Findlow H, et al. Kinetics of antibody persistence following administration of a combination meningococcal serogroup C and Haemophilus influenzae
type b conjugate vaccine in healthy infants in the United Kingdom primed with a monovalent meningococcal serogroup C vaccine. Clin Vaccine Immunol. 2010;17:154–159
23. Díez-Domingo J, Cantarino MV, Torrentí JM, et al.MenC Study Group. A randomized, multicenter, open-label clinical trial to assess the immunogenicity of a meningococcal C vaccine booster dose administered to children aged 14 to 18 months. Pediatr Infect Dis J. 2010;29:148–152
24. Burrage M, Robinson A, Borrow R, et al. Effect of vaccination with carrier protein on response to meningococcal C conjugate vaccines and value of different immunoassays as predictors of protection. Infect Immun. 2002;70:4946–4954
25. Dagan R, Eskola J, Leclerc C, et al. Reduced response to multiple vaccines sharing common protein epitopes that are administered simultaneously to infants. Infect Immun. 1998;66:2093–2098
26. Kitchin NR, Southern J, Morris R, et al. Evaluation of a diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae
type b vaccine given concurrently with meningococcal group C conjugate vaccine at 2, 3 and 4 months of age. Arch Dis Child. 2007;92:11–16
27. Tejedor JC, Moro M, Ruiz-Contreras J, et al.Spanish DTaP-HBV-IPV-097 Study Group. Immunogenicity and reactogenicity of primary immunization with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type b
vaccine coadministered with two doses of a meningococcal C-tetanus toxoid conjugate vaccine. Pediatr Infect Dis J. 2006;25:713–720
28. English M, MacLennan JM, Bowen-Morris JM, et al. A randomised, double-blind, controlled trial of the immunogenicity and tolerability of a meningococcal group C conjugate vaccine in young British infants. Vaccine. 2000;19:1232–1238
29. Lee LH, Blake MS. Effect of increased CRM197
carrier protein dose on meningococcal C bactericidal antibody response. Clin Vaccine Immunol. 2012;19:551–556
30. Pöllabauer EM, Petermann R, Ehrlich HJ. The influence of carrier protein on the immunogenicity of simultaneously administered conjugate vaccines in infants. Vaccine. 2009;27:1674–1679
31. Booy R, Richmond P, Nolan T, et al. Immediate and longer term immunogenicity of a single dose of the combined Haemophilus influenzae
type b-Neisseria meningitidis
serogroup C-tetanus toxoid conjugate vaccine in primed toddlers 12 to 18 months of age. Pediatr Infect Dis J. 2011;30:340–342
32. Kelly DF, Snape MD, Clutterbuck EA, et al. CRM197-conjugated serogroup C meningococcal capsular polysaccharide, but not the native polysaccharide, induces persistent antigen-specific memory B cells. Blood. 2006;108:2642–2647
33. Snape MD, Kelly DF, Salt P, et al. Serogroup C meningococcal glycoconjugate vaccine in adolescents: persistence of bactericidal antibodies and kinetics of the immune response to a booster vaccine more than 3 years after immunization. Clin Infect Dis. 2006;43:1387–1394
34. McVernon J, Johnson PD, Pollard AJ, et al. Immunologic memory in Haemophilus influenzae
b conjugate vaccine failure. Arch Dis Child. 2003;88:379–383
35. Blanchard Rohner G, Snape MD, Kelly DF, et al. The magnitude of the antibody and memory B cell responses during priming with a protein-polysaccharide conjugate vaccine in human infants is associated with the persistence of antibody and the intensity of booster response. J Immunol. 2008;180:2165–2173
36. McVernon J, MacLennan J, Pollard AJ, et al. Immunologic memory with no detectable bactericidal antibody response to a first dose of meningococcal serogroup C conjugate vaccine at four years. Pediatr Infect Dis J. 2003;22:659–661
37. Pollard AJ, Perrett KP, Beverley PC. Maintaining protection against invasive bacteria with protein-polysaccharide conjugate vaccines. Nat Rev Immunol. 2009;9:213–220
meningococcal; conjugate vaccine; priming; immune response
Supplemental Digital Content
© 2013 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.