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Original Contribution |

Immunogenicity and Safety of a Combination Pneumococcal-Meningococcal Vaccine in Infants:  A Randomized Controlled Trial FREE

Jim P. Buttery, FRACP; Anna Riddell, MRCPCH; Jodie McVernon, PhD; Tracey Chantler, RN; Laura Lane, RN; Jane Bowen-Morris, RN; Linda Diggle, MSc; Rhonwen Morris, MPH; Anthony Harnden, FRCPCH; Steven Lockhart, DM; Andrew J. Pollard, PhD; Keith Cartwright, FRCPath; E. Richard Moxon, FRCP
[+] Author Affiliations

Author Affiliations: Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics (Drs Buttery, Riddell, McVernon, Pollard, and Moxon and Mss Chantler, Lane, Bowen-Morris, and Diggle) and Department of Primary Health Care (Dr Harnden), University of Oxford, Churchill Hospital, Headington, Oxford, UK; Public Health Laboratory, Gloucestershire Royal Hospital, Gloucester, UK (Ms Morris and Dr Cartwright); and Wyeth Vaccines, Huntercombe Lane South, Taplow, Maidenhead, UK (Dr Lockhart). Dr Buttery is now with the Department of General Medicine, Murdoch Childrens Research Institute, University of Melbourne Department of Paediatrics, Royal Children’s Hospital, Melbourne, Australia.

More Author Information
JAMA. 2005;293(14):1751-1758. doi:10.1001/jama.293.14.1751.
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Published online

Context The success of conjugate vaccines in decreasing invasive disease due to Streptococcus pneumoniae and group C Neisseria meningitidis has placed pressure on crowded infant immunization schedules, making development of combination vaccines a priority.

Objective To determine the safety and immunogenicity of a combination 9-valent pneumococcal–group C meningococcal conjugate candidate vaccine (Pnc9-MenC) administered as part of the routine UK infant immunization schedule at ages 2, 3, and 4 months.

Design, Setting, and Participants Phase 2 randomized controlled trial conducted from August 2000 to January 2002 and enrolling 240 healthy infants aged 7 to 11 weeks from 2 UK centers, with home follow-up visits at ages 2, 3, 4, and 5 months.

Intervention Pnc9-MenC (n = 120) or monovalent group C meningococcal conjugate vaccine (MenC) (n = 120) administered in addition to routine immunizations (diphtheria and tetanus toxoids and whole-cell pertussis [DTwP], Haemophilus influenzae type b [Hib] polyribosylribitol phosphate-tetanus toxoid protein conjugate, oral polio vaccine).

Main Outcome Measures Group C meningococcal immunogenicity measured by serum bactericidal titer (SBT) 1 month following the third dose; rates of postimmunization reactions.

Results MenC component immunogenicity was reduced in the Pnc9-MenC vs the MenC group (geometric mean SBT, 179 [95% confidence interval {CI}, 133-243] vs 808 [95% CI, 630-1037], respectively; P<.001). The proportion with group C meningococcal SBT greater than 1:8 was lower in the Pnc9-MenC vs the MenC group (95% vs 100%, P = .05). The geometric mean concentration of antibodies to concomitantly administered Hib vaccine was reduced in the Pnc9-MenC vs the MenC group (2.11 [95% CI, 1.57-2.84] μg/mL vs 3.36 [95% CI, 2.57-4.39] μg/mL; P = .02), as were antibodies against diphtheria (0.74 [95% CI, 0.63-0.87] μg/mL vs 1.47 [95% CI, 1.28-1.69] μg/mL; P<.001). Pnc9-MenC was immunogenic for each of 9 contained pneumococcal serotypes, with responses greater than 0.35 μg/mL observed in more than 88% of infants. Increased irritability and decreased activity were observed after the third dose in the Pnc9-MenC group.

Conclusions Pnc9-MenC combination vaccine administered to infants at ages 2, 3, and 4 months demonstrated reduced group C meningococcal immunogenicity compared with MenC vaccine. The immunogenicity of concomitantly administered Hib and DTwP vaccines was also diminished. The Pnc9-MenC vaccine was safe and immunogenic for all contained pneumococcal serotypes. The reduced MenC immunogenicity may limit the development of the Pnc9-MenC vaccine.

Figures in this Article

The development of immunogenic vaccines against major encapsulated pathogens of childhood has dramatically decreased the rates of invasive disease caused by Haemophilus influenzae type b, serogroup C Neisseria meningitidis, and Streptococcus pneumoniae in the developed countries fortunate enough to be able to afford the vaccines. Since the introduction of a monovalent serogroup C meningococcal glycoconjugate vaccine (MenC) into the UK routine immunization schedule in November 1999, group C meningococcal disease has decreased by 87% in the ages targeted for vaccination, with estimated vaccine efficacy of 90%.1 Within 2 years of the introduction of a 7-valent pneumococcal glycoconjugate vaccine into the recommended infant schedule in the United States, there was a 69% reduction in culture-positive invasive pneumococcal disease in children younger than 2 years.2 However, outside North America, and especially in developing nations where the toll of pneumococcal disease is highest, the 7-valent pneumococcal glycoconjugate vaccine does not cover all of the prevalent serotypes. In particular, the inclusion of serotype 1 is considered vital to achieve optimal coverage internationally.

The advent of these efficacious and safe vaccines has increased pressure on crowded infant immunization schedules. Infants in the United States receive up to 20 separate vaccine injections over 5 immunization encounters at ages 2, 4, 6, 12, and 18 months to protect against disease due to hepatitis B, diphtheria, tetanus, pertussis, polio, measles, mumps, rubella, varicella, H influenzae type b, and pneumococcus. The UK immunization schedule differs in having an accelerated infant schedule at ages 2, 3, and 4 months and no 18-month booster visit. Infants in the United Kingdom also do not receive hepatitis B, varicella, or pneumococcal vaccine, but routinely do receive 3 doses of MenC vaccine. The inclusion of MenC would add a further 3 to 4 doses to the US regimen, while the inclusion of pneumococcal glycoconjugate vaccine would add at least 3 doses for UK infants. Many other countries, including Australia, Canada, and western European nations, have incorporated MenC and/or pneumococcal glycoconjugate vaccines into their recommended schedules.

In anticipation of the recommendation of both these vaccines in many developed countries, the development of combination vaccines has become a priority. The combining of pneumococcal and meningococcal conjugate vaccines has the potential to spare US infants up to 4 extra injections by age 18 months and to decrease parental and clinician concerns about the number of vaccinations in early childhood. In the United Kingdom, where vaccines are routinely administered in just 2 syringes at each vaccination visit, a combination meningococcal-pneumococcal vaccine would avoid the need to increase from 2 to 3 injections at each visit and thereby make the addition of pneumococcal vaccine to the schedule more acceptable. This report describes the immunogenicity and safety of a combination 9-valent pneumococcal–group C meningococcal polysaccharide-protein conjugate candidate vaccine (Pnc9-MenC) given to UK infants at ages 2, 3, and 4 months.

Participants and Recruitment

The current study was a phase 2 randomized controlled trial conducted from August 2000 to January 2002 and enrolling healthy infants aged 7 to 11 weeks from 2 centers in Oxford and Gloucester, United Kingdom. In Oxford, up to 2 letters were sent to parents of eligible infants belonging to general practice lists of 16 participating practices in Oxfordshire, inviting them to contact the investigators regarding the study. Parents interested in the study were visited at home by research nurses. If families wished to participate, informed written consent was obtained, followed by additional home visits. In Gloucester, parents of eligible children in the practice were sent letters of invitation to participate, and parents of eligible infants who expressed an interest in the study were contacted by research nurses. Written consent was obtained at 1 of 14 participating practices, and subsequent visits also occurred there. Exclusion criteria included known immunosuppression, previous vaccination (apart from BCG or hepatitis B vaccines), and confirmed invasive meningococcal or pneumococcal disease. The study was approved by the Central Oxford Research Ethics Committee (COREC 00.043) and the Gloucestershire Local Research Ethics Committee (GLREC 99/1049).

Visits and Vaccines

The infants were visited at ages 2, 3, 4, and 5 months, with a window of 28 to 42 days between visits. Infants were immunized at 2, 3, and 4 months with diphtheria and tetanus toxoids and whole-cell pertussis (DTwP) vaccine (Aventis, Lyon, France), 0.5 mL, admixed with H influenzae type b (Hib) polyribosylribitol phosphate-tetanus toxoid protein conjugate (ActHib; Aventis), 0.5 mL, administered intramuscularly in the right anterolateral thigh. Infants also received oral polio vaccine, 2 drops administered orally. Infants were randomized in a 1:1 ratio at study entry to receive in their left anterolateral thigh either Pnc9-MenC (Wyeth Vaccines, Maidenhead, UK), 0.5 mL intramuscularly, or MenC (Meningitec; Wyeth Vaccines), 0.5 mL intramuscularly, at each vaccine visit. Randomization was performed by a computer-generated randomization list in blocks of 6. The study was not blinded because the Pnc9-MenC (lyophilized) and MenC (preprepared in the syringe) vaccines were visually different.

The Pnc9-MenC vaccine was a lyophilized preparation supplied in single-dose vials. Each 0.5-mL dose contained 2 μg of pneumococcal saccharide conjugates 1, 4, 5, 9V, 14, 18C, 19F, and 23F; 4 μg of pneumococcal saccharide conjugate 6B; 10 μg of meningococcal group C oligosaccharide; and approximately 38.5 μg of cross-reacting material 197 (CRM197) carrier protein (a nontoxic variant of diphtheria toxin) with 0.5 mg of aluminum phosphate (0.125 mg elemental aluminum) as adjuvant. The MenC is a conjugate vaccine containing meningococcal serogroup C oligosaccharide conjugated to CRM197. Each 0.5-mL dose contained 10 μg of meningococcal group C oligosaccharide, 15 μg of CRM197 carrier protein, and 0.5 mg of aluminum phosphate (0.125 mg elemental aluminum) as adjuvant. The MenC component in the Pnc9-MenC vaccine was derived from a different manufacturer lot than that in the MenC vaccine. Venipuncture was performed at the 2- and 5-month visits, and 2.5 to 5.0 mL of blood was obtained for serologic assays.

Safety Evaluation

Following each immunization visit, infants were observed for 20 minutes for immediate hypersensitivity reactions, and parents completed diaries for the day of immunization and the 3 following days, recording all local and systemic adverse events. Local reactions solicited included tenderness and presence and size of erythema and induration. Systemic events solicited included drowsiness, change in appetite, irritability, persistent crying, changes in activity level, and use of antipyretic medication. Parents measured their child’s axillary temperature on the evening after vaccination and the subsequent 3 evenings. Fever at any other time in the 4-day period was also recorded. Information on adverse events was actively obtained by research nurses using telephone calls up to twice in the week after vaccination and monthly visits up to age 5 months (1 month after the last vaccination). All events requiring a visit to a clinician, as well as all serious adverse events, were reported. Temperature greater than 39.5°C per axilla within 48 hours and prolonged inconsolable or high-pitched screaming for more than 3 hours following vaccination were exclusion criteria for further study doses.

Serologic Assays

Serum samples were tested by serum bactericidal assay (SBA) for functional antibody against group C N meningitidis as previously described, using baby rabbit complement, at the Public Health Laboratory Service Meningococcal Reference Unit, Manchester, UK.3 SBA titers were expressed as the reciprocal serum dilution yielding 50% or greater killing after 90 minutes. SBA titers less than 4 were designated a value of 2. The geometric mean titer (GMT) and the proportion in each group exceeding titers of the protective correlate of 1:8 and the suggested long-term protected correlate of 1:128 were determined for each group. Enzyme-linked immunosorbent assays (ELISAs) were also performed for antibody responses to meningococcal group C capsular polysaccharide, diphtheria, tetanus, pertussis (pertussis toxin, filamentous hemagglutinin), and Hib as previously described.4 For diphtheria and tetanus, the accepted protective correlate of 0.1 μg/mL was used, while for Hib the short-term (0.15 μg/mL) and long-term (1.0 μg/mL) correlates were used.5 Polio types 1, 2, and 3 responses were assessed by neutralization assay.4 Geometric mean concentrations (GMCs) were determined for each group, and the proportions reaching predetermined protective cutoff levels for each assay were also described.

Pneumococcal serotype-specific antibody concentrations were measured using IgG ELISAs to detect antibody to pneumococcal capsular polysaccharides types 1, 4, 5, 6B, 9V, 14, 18C, 19F, and 23F.6 A number of protective cutoffs have been suggested, with 0.2 μg/mL and 0.35 μg/mL most often proposed as short-term protective correlates. Of these, the more stringent 0.35 μg/mL was used in this study, but 0.2 μg/mL is also presented. The long-term correlate used was 1.0 μg/mL.

All assays were performed at Wyeth Laboratories, Rochester, NY, apart from SBAs against group C N meningitidis. Laboratory staff were blinded to participant allocation.

Statistical Analyses

Antibody levels were log-transformed, and GMTs and GMCs with 95% confidence intervals (CIs) calculated. The t test was used to compare postvaccination GMTs (MenC SBA) or GMCs between groups. The χ2 test was used to compare proportions achieving predetermined protective levels between groups. The χ2 test was also used to compare proportions of infants with adverse reactions between groups.

The predicted sample was based on the primary immunogenicity measure of meningococcal group C SBA after dose 3 for a range of threshold values from 1:8 to 1:256. Based on previous data showing that more than 95% of infants in the MenC control group had SBTs greater than 1:8, 100 per group were required to demonstrate noninferiority of Pnc9-MenC, with α=.05 and power of 80%.4 Allowing for a 20% dropout rate, a sample size of 240 infants was selected. Analyses were performed using Intercooled Stata version 8.0 (Stata Corp, College Station, Tex).

Two hundred forty infants were randomized between August 2000 and September 2001. The Pnc9-MenC group contained 66 male and 54 female infants of mean age 1.96 months; the MenC group contained 63 male and 57 female infants of mean age 1.92 months. The participant flow is summarized in the Figure.

Figure. Flow Diagram of Study Groups
Graphic Jump Location

MenC indicates monovalent group C meningococcal conjugate; Pnc9-MenC, 9-valent pneumococcal–group C meningococcal conjugate.
*Two infants withdrawn following first vaccination, 1 due to fever and 1 due to prolonged crying and fever; 3 infants withdrawn following second vaccination (2 due to prolonged crying, 1 due to fever).
†Withdrawn following second vaccination due to prolonged crying.

Safety

Both Pnc9-MenC and MenC were well tolerated, with no immediate adverse events. Two infants in the Pnc9-MenC group were withdrawn following the first vaccination at 2 months, 1 due to fever and 1 due to prolonged crying and fever. Four infants were withdrawn after the second vaccination at 3 months, 3 due to prolonged crying (2 Pnc9-MenC, 1 MenC) and 1 due to fever (Pnc9-MenC). Table 1 describes the proportions in each group experiencing local and systemic adverse events. Local reactions in the study vaccine limb were uncommon in both groups. Temperature greater than 38°C per axilla was reported in 42 infants (35.3%) receiving Pnc9-MenC and in 32 (26.7%) of those receiving MenC (P = .15). Irritability (65.2% vs 48.7%, P = .02) and decreased activity (33.0% vs 20.2%, P = .03) were reported more frequently after the third dose in the Pnc9-MenC group than in the MenC group, but not after other doses.

Table Graphic Jump LocationTable 1. Reactogenicity of Pnc9-MenC and MenC Vaccines Given Concurrently With DTwP/Hib and OPV Vaccines in Infants Aged 2, 3, and 4 Months
Immunogenicity

The Pnc9-MenC vaccine was less immunogenic than the MenC vaccine in induction of serogroup C meningococcal polysaccharide antibodies as determined at age 5 months by both SBA and ELISA (SBA GMT, 179 [95% CI, 133-243] for Pcn9-MenC vs 808 [95% CI, 630-1037] for MenC; P<.001) (Table 2). The proportions of infant serum samples with serogroup C meningococcal SBA titers greater than 1:128 and greater than 1:8 were also lower in this group.

Table Graphic Jump LocationTable 2. Immunogenicity of the MenC Vaccine Component and Concomitant Vaccines 1 Month After a 3-Dose Immunization Series*

Geometric mean Hib antibody concentrations following 3 doses of Hib vaccine were also reduced in the Pnc9-MenC group when compared with the MenC group (2.11 [95% CI, 1.57-2.84] μg/mL vs 3.36 [95% CI, 2.57-4.39] μg/mL; P = .02) (Table 2). However, the lower GMC was not reflected in differences in the proportions of serum samples in the 2 groups exceeding 0.15 μg/mL and 1.0 μg/mL at 5 months of age. Antidiphtheria antibody levels also differed between the groups when measured at 5 months, with lower GMC achieved by the Pnc9-MenC group when compared with the MenC group (0.74 [95% CI, 0.63-0.87] μg/mL vs 1.47 [95% CI, 1.28-1.69] μg/mL, respectively; P<.001) (Table 2), although all infants in both groups surpassed the protective cutoff of 0.1 μg/mL. Antitetanus GMCs did not differ significantly. There were no differences between the groups in responses to the other concomitantly administered vaccine antigens at age 5 months following the 3-dose routine primary vaccine series.

All pneumococcal serotypes contained in the vaccine were immunogenic (Table 3), with at least 88% of recipients developing postvaccination GMCs greater than 0.35 μg/mL to each serotype. The greatest proportions developing GMCs greater than 1.0 μg/mL were achieved for serotypes 1, 4, 14, and 19F and the lowest for serotypes 6B and 9V.

Table Graphic Jump LocationTable 3. Infants Achieving Putative Protective Pneumococcal Serotype-Specific Antibody Concentrations 1 Month After Primary Immunization Series*

This study describes the first infant trial of a candidate combination Pnc9-MenC conjugate vaccine. It illustrates the unpredictability of immunogenicity when combining multivalent vaccines, each immunogenic in separate form. The reduced immunogenicity of the serogroup C meningococcal component of Pnc9-MenC as well as concomitantly administered Hib and diphtheria may limit its further development.

We found Pnc9-MenC to be well tolerated and immunogenic for the pneumococcal serotypes contained in the vaccine. While absolute pneumococcal serotype-specific serologic correlates of protection are unknown, at least 88% of infants achieved antibody concentrations of 0.35 μg/mL or greater 1 month after their third dose for each serotype.7 The immunogenicity results for the serotypes also contained in the licensed 7-valent pneumococcal conjugate Prevnar (Wyeth Vaccines) (4, 6B, 9V, 14, 18C, 19F, and 23F) are similar to those obtained after 3 doses at ages 2, 4, and 6 months with that vaccine.8 Good immunogenicity was also achieved for the additional serotype 1, but relatively lower GMCs were found for serotype 5, as observed with other 9- and 11-valent pneumococcal vaccines using varying conjugating proteins.911

The laboratory correlate of natural protection against invasive meningococcal group C disease was established during military recruit studies in the 1960s. Goldschneider et al12 found the functional assay of group C meningococcal SBA titer to correspond with clinical protection, with a titer greater than 1:8 protective. Enzyme-linked immunosorbent assay levels of antibody to meningococcal group C capsular polysaccharide were found to correspond with this assay, with the protective cutoff at 2 μg/mL.4 These assay levels formed the basis on which glycoconjugate MenC vaccines were licensed and introduced into the UK national immunization schedule in the absence of efficacy data. Similar protective levels of antibody to H influenzae type b were also accepted following polysaccharide vaccine studies, with a postvaccination level greater than 0.15 μg/mL corresponding to short-term protection and greater than 1.00 μg/mL with long-term protection. Laboratory correlates of protection against pneumococcal disease have yet to be agreed upon.

The Pnc9-MenC group achieved lower SBA titers to group C meningococcus than the MenC group, with a lower GMT. Fewer in the Pnc9-MenC group exceeded the protective threshold titer of 1:8 and the putative threshold titer of 1:128. Geometric mean concentrations of anticapsular polysaccharide antibody measured by ELISA were also lower in the Pnc9-MenC group, and fewer achieved the putative protective threshold of 2 μg/mL. The incorporation of different polysaccharide antigens into a multivalent conjugate vaccine is technically difficult and can unpredictably affect the immunogenicity of individual components. Previous hypotheses for unexpectedly low immunogenicity of conjugate vaccines have included carrier-induced epitope suppression, with immune responses directed against the carrier protein (here, the mutant diphtheria toxoid CRM197) suppressing the response to the covalently bound polysaccharide.13 The increased amount of carrier protein in each Pnc9-MenC dose (38 μg vs 10 μg in MenC) offers some support to this theory. At least 2 manufacturers have used mixed carrier proteins for candidate conjugate vaccines to lessen the impact of immune responses to carrier protein.9,14 The MenC component of the Pnc9-MenC vaccine did come from a different manufacturer lot than the MenC used in the control group. While it is possible for minor immunogenicity differences to occur, it is unlikely that this is responsible for the observed difference, considering the additional effects on Hib and diphtheria immunogenicity in the Pnc9-MenC group.

Haemophilus influenzae type b antibody responses were also unexpectedly diminished in the Pnc9-MenC group. The Hib vaccine used in this trial was administered concurrently with the study vaccines in the opposite limb, admixed with DTwP. This reduction was not matched by reduced proportions achieving short-term protective titers greater than 0.15 μg/mL.5 Fewer in the Pnc9-MenC group reached long-term protective titers greater than 1.00 μg/mL; however, the difference in proportions between groups was not significant. Similar reductions have been described when combination vaccines containing diphtheria-tetanus-acellular pertussis and Hib have been evaluated.15 While the Hib conjugate vaccine used in the current study was coadministered in the same syringe as DTwP vaccine, it was administered at a separate site than the Pnc9-MenC or MenC vaccines, ruling out any physico-chemical interference. Neither can the phenomenon of carrier-induced epitope suppression explain this finding, as Pnc9-MenC and MenC vaccines both use the mutant diphtheria toxoid CRM197 as their conjugate protein.16 Nonepitope-specific suppression has been described in adults receiving Hib conjugate vaccines. Barington et al16 described reductions in both Hib and tetanus toxoid antibody titers in patients receiving Hib-tetanus toxoid glycoconjugate vaccine who had been prevaccinated with Hib-diphtheria toxoid glycoconjugate vaccine 28 days earlier, compared with those who had not been prevaccinated. The same effect on Hib and diphtheria toxoid antibody titers was observed among patients prevaccinated with Hib-tetanus toxoid who were receiving Hib-diphtheria toxoid.

The impact on Hib vaccine immunogenicity is of particular interest in the United Kingdom, given the observed increase there in Hib vaccine failures in recent years. Rapid waning of initial titers has been described for all glycoconjugate vaccines, and a lower initial serologic response may result in more rapid decline in titers.4,17 Similarly, recent analysis of the effectiveness of the national MenC vaccination program in the United Kingdom has identified a potential lack of protection beyond 1 year after vaccination for those vaccinated as infants (at ages 2, 3, and 4 months), despite immunological memory being demonstrated with this regimen.18 In this context, a combination vaccine offering lower initial group C meningococcal immunogenicity would be unlikely to be acceptable. These issues are likely to be of particular concern where booster doses are not part of the immunization schedule. It is not known whether similar effects on Hib and MenC immunogenicity would be observed when used outside of the UK “accelerated” infant immunization schedule, which has only 1 month of separation between each dose, compared with 2 months of separation for US infants.

The effect of Pnc9-MenC on diphtheria immunogenicity is also unexpected. As a mutant diphtheria toxoid, the protein conjugate CRM197 used in both study vaccines can independently induce antibody against diphtheria.19 The Pnc9–MenC vaccine contained nearly twice as much CRM197 (approximately 38.5 μg) compared with MenC (20 μg). At each of 3 immunization visits only 1 month apart, children received in addition to the study vaccines a further 30 IU of diphtheria as part of DTwP vaccine. However, the serum samples of all vaccinees exceeded the protective threshold of 0.01 IU/mL and the reduced diphtheria immunogenicity is probably of no clinical significance.

The sample size of this study was selected for the primary immunological end point of group C meningococcal SBA cutoff levels. As a result, the ability to detect adverse events associated with vaccination is limited only to common adverse events. The proportions of children with systemic reactions were similar to those expected following whole-cell pertussis–containing vaccines and were consistent with previously described rates post DTwP vaccination,4 although irritability and decreased activity were more common after the third dose of Pnc9-MenC compared with MenC. In addition, more children in the Pnc9-MenC group were withdrawn for prolonged fever or crying (5 vs 1). Uncommon adverse events require ongoing cumulative monitoring across all clinical stages of development, including larger phase 3 trials, to enable associations to be detected. Rare associations may not be detected until postlicensure surveillance.

Although the study was randomized, the inability to blind clinical investigators and participating parents to vaccines given (due to visually different study vaccines) is a further limitation, with the potential for bias in reporting of adverse events. Laboratory staff performing immunological assays remained blinded to participant allocation. The high rate of refusal to participate, while typical of vaccine trials in developed countries, potentially diminishes the generalizability of these findings. Finally, we did not compare the combination vaccine with separate injections of MenC and Pnc9, as MenC is the standard currently used in the United Kingdom. It is possible that the administration of the vaccines separately may have had the same effect on immunogenicity to meningococcus or coadministered vaccine antigens as observed here when given as a combination vaccine. This possibility may warrant further study.

Since the pneumococcal serotype distribution associated with invasive disease varies around the world, increasing the number of serotypes in the pneumococcal conjugate vaccine is critical in generalizing its potential benefit to many nations, especially developing nations where most of the estimated 1.2 million childhood pneumococcal deaths occur each year.20 Although the addition of serotypes 1 and 5 only increases serotype coverage for invasive bacteremic episodes from 82.2% to 82.6% in US children younger than 2 years,21 in the United Kingdom this potential coverage is estimated to increase from 79.3% to 86.7% in children younger than 5 years when compared with the 7-valent vaccine.22 In African nations where invasive isolates have been serotyped, adding serotypes 1 and 5 boosts coverage from 72% to 91% over that potentially offered by the 7-valent vaccine.23

These results highlight the unpredictability of immune responses to individual vaccine antigens after incorporating multiple antigens into combination vaccines and underline the importance of assessing the immunogenicity of all coadministered vaccine antigens in prelicensure trials. The Pnc9-MenC vaccine as tested may not be a suitable replacement for individual MenC or pneumococcal glycoconjugate vaccines.

Corresponding Author: Jim P. Buttery, FRACP, Paediatric Infectious Diseases Unit, Department of General Medicine, Murdoch Childrens Research Institute, University of Melbourne Department of Paediatrics, Royal Children’s Hospital, Flemington Road, Parkville 3052, Victoria, Australia (jim.buttery@rch.org.au).

Author Contributions: Dr Buttery had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Buttery, Diggle, Morris, Lockhart, Cartwright, Moxon.

Acquisition of data: Buttery, Riddell, Chantler, Lane, Bowen-Morris, Morris, Harnden, Pollard.

Analysis and interpretation of data: Buttery, McVernon, Lockhart, Pollard, Moxon.

Drafting of the manuscript: Buttery, Harnden, Pollard.

Critical revision of the manuscript for important intellectual content: Buttery, Riddell, McVernon, Chantler, Lane, Bowen-Morris, Diggle, Morris, Lockhart, Pollard, Cartwright, Moxon.

Statistical analysis: Buttery, McVernon.

Obtained funding: Lockhart, Moxon.

Administrative, technical, or material support: Buttery, Riddell, Chantler, Lane, Bowen-Morris, Diggle, Morris, Lockhart, Pollard.

Study supervision: Buttery, Pollard, Cartwright.

Financial Disclosures: Dr Buttery serves as an investigator for clinical trials conducted on behalf of the Murdoch Childrens Research Institute (sponsored by GlaxoSmithKline, Merck, and MedImmune); has served as an investigator for clinical trials conducted on behalf of Oxford University (sponsored by Aventis Pasteur-Merck Sharpe and Dohme, Aventis Pasteur, Chiron Vaccines, and Wyeth Vaccines); has received assistance to attend scientific meetings from GlaxoSmithKline, Aventis Pasteur-Merck Sharpe and Dohme, Aventis Pasteur, and Wyeth Vaccines; and has served as a consultant for GlaxoSmithKline and Wyeth Vaccines. Industry honoraria for consulting, lecturing, or writing are paid directly to an educational fund held by Murdoch Childrens Research Institute. Dr Pollard serves as chief investigator for clinical trials conducted on behalf of Oxford University (sponsored by Aventis Pasteur-Merck Sharpe and Dohme, Chiron Vaccines, GlaxoSmithKline, Sanofi-Aventis, and Wyeth Vaccines) and has received assistance from Aventis Pasteur-Merck Sharpe and Dohme, Chiron Vaccines, and Wyeth Vaccines to attend scientific meetings. Industry honoraria for lecturing or writing are paid directly to an independent charity or an educational fund held by the Department of Pediatrics, University of Oxford. Dr Pollard is an inventor on a patent application in the area of meningitis B vaccines and serves as chair of the scientific panel of Spencer Dayman Meningitis UK, a registered charity. Dr Moxon has served as consultant for Aventis Pasteur, Chiron Vaccines, Acambis, and Renaissance; has received support to attend scientific meetings from Wyeth-Lederle, Aventis Pasteur, and Chiron Vaccines; and currently serves on the advisory board for Chiron Vaccines.

Funding/Support: This study was funded by Wyeth Vaccines.

Role of the Sponsor: Analysis was performed independently by the investigators using the complete data set, which was provided by Wyeth Vaccines. Wyeth was involved in the design of the study; monitored conduct of the study including data collection and management; and reviewed and approved the manuscript.

Acknowledgment: We thank the families of participating children, Shirley Ashmore and Carole Barr for administrative assistance, Diane Webb, Wendy Nedoma, Gail Breeze, Jen Jones, Anne Stevens, Anne Maher, Angela Hogan, Maggie Boardman, and Karen Brown for their contributions, and Suzana Vidmar for statistical advice.

Acknowledgment: We thank the families of participating children, Shirley Ashmore and Carole Barr for administrative assistance, Diane Webb, Wendy Nedoma, Gail Breeze, Jen Jones, Anne Stevens, Anne Maher, Angela Hogan, Maggie Boardman, and Karen Brown for their contributions, and Suzana Vidmar for statistical advice.

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Lee LH, Frasch CE, Falk LA, Klein DL, Deal CD. Correlates of immunity for pneumococcal conjugate vaccines.  Vaccine. 2003;21:2190-2196
PubMed   |  Link to Article
Black S, Shinefield H, Fireman B.  et al. Northern California Kaiser Permanente Vaccine Study Center Group.  Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children.  Pediatr Infect Dis J. 2000;19:187-195
PubMed   |  Link to Article
Dagan R, Kayhty H, Wuorimaa T.  et al.  Tolerability and immunogenicity of an eleven valent mixed carrier Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid or tetanus protein conjugate vaccine in Finnish and Israeli infants.  Pediatr Infect Dis J. 2004;23:91-98
PubMed   |  Link to Article
Puumalainen T, Zeta-Capeding MR, Kayhty H.  et al.  Antibody response to an eleven valent diphtheria-and tetanus-conjugated pneumococcal conjugate vaccine in Filipino infants.  Pediatr Infect Dis J. 2002;21:309-314
PubMed   |  Link to Article
Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.  N Engl J Med. 2003;349:1341-1348
PubMed   |  Link to Article
Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus, I: the role of humoral antibodies.  J Exp Med. 1969;129:1307-1326
PubMed   |  Link to Article
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
PubMed   |  Link to Article
Anderson P, Treanor J, Porcelli S, Pichichero M. Non-interference between two protein carriers when used with the same polysaccharide for pneumococcal conjugate vaccines in 2-year-old children.  Vaccine. 2003;21:1554-1559
PubMed   |  Link to Article
Greenberg DP, Wong VK, Partridge S.  et al.  Immunogenicity of a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine when mixed with a diphtheria-tetanus-acellular pertussis-hepatitis B combination vaccine.  Pediatr Infect Dis J. 2000;19:1135-1140
PubMed   |  Link to Article
Barington T, Skettrup M, Juul L, Heilmann C. Non-epitope-specific suppression of the antibody response to Haemophilus influenzae type b conjugate vaccines by preimmunization with vaccine components.  Infect Immun. 1993;61:432-438
PubMed
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
PubMed   |  Link to Article
Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction.  Lancet. 2004;364:365-367
PubMed   |  Link to Article
McVernon J, Maclennan J, Clutterbuck E, Buttery J, Moxon ER. Effect of infant immunisation with meningococcus serogroup C-CRM(197) conjugate vaccine on diphtheria immunity and reactogenicity in pre-school aged children.  Vaccine. 2003;21:2573-2579
PubMed   |  Link to Article
World Health Organization.  Vaccine Research and Development: Report of a Technical Review Group Meeting, June 9-10, 1997Geneva, Switzerland: WHO; 1997:32-36
Cronin WA, Germanson TP, Donowitz LG. Intravascular catheter colonization and related bloodstream infection in critically ill neonates.  Infect Control Hosp Epidemiol. 1990;11:301-308
PubMed   |  Link to Article
Sleeman K, Knox K, George R.  et al.  Invasive pneumococcal disease in England and Wales: vaccination implications.  J Infect Dis. 2001;183:239-246
PubMed   |  Link to Article
Huebner RE, Wasas AD, Klugman KP. Trends in antimicrobial resistance and serotype distribution of blood and cerebrospinal fluid isolates of Streptococcus pneumoniae in South Africa, 1991-1998.  Int J Infect Dis. 2000;4:214-218
PubMed   |  Link to Article

Figures

Figure. Flow Diagram of Study Groups
Graphic Jump Location

MenC indicates monovalent group C meningococcal conjugate; Pnc9-MenC, 9-valent pneumococcal–group C meningococcal conjugate.
*Two infants withdrawn following first vaccination, 1 due to fever and 1 due to prolonged crying and fever; 3 infants withdrawn following second vaccination (2 due to prolonged crying, 1 due to fever).
†Withdrawn following second vaccination due to prolonged crying.

Tables

Table Graphic Jump LocationTable 1. Reactogenicity of Pnc9-MenC and MenC Vaccines Given Concurrently With DTwP/Hib and OPV Vaccines in Infants Aged 2, 3, and 4 Months
Table Graphic Jump LocationTable 2. Immunogenicity of the MenC Vaccine Component and Concomitant Vaccines 1 Month After a 3-Dose Immunization Series*
Table Graphic Jump LocationTable 3. Infants Achieving Putative Protective Pneumococcal Serotype-Specific Antibody Concentrations 1 Month After Primary Immunization Series*

References

Balmer P, Borrow R, Miller E. Impact of meningococcal C conjugate vaccine in the UK.  J Med Microbiol. 2002;51:717-722
PubMed
Whitney CG, Farley MM, Hadler J.  et al.  Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine.  N Engl J Med. 2003;348:1737-1746
PubMed   |  Link to Article
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
PubMed
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
PubMed   |  Link to Article
Kayhty H. Immunogenicity assays and surrogate markers to predict vaccine efficacy.  Dev Biol Stand. 1998;95:175-180
PubMed
Quataert S, Martin D, Anderson P.  et al.  A multi-laboratory evaluation of an enzyme-linked immunoassay quantitating human antibodies to Streptococcus pneumoniae polysaccharides.  Immunol Invest. 2001;30:191-207
PubMed   |  Link to Article
Lee LH, Frasch CE, Falk LA, Klein DL, Deal CD. Correlates of immunity for pneumococcal conjugate vaccines.  Vaccine. 2003;21:2190-2196
PubMed   |  Link to Article
Black S, Shinefield H, Fireman B.  et al. Northern California Kaiser Permanente Vaccine Study Center Group.  Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children.  Pediatr Infect Dis J. 2000;19:187-195
PubMed   |  Link to Article
Dagan R, Kayhty H, Wuorimaa T.  et al.  Tolerability and immunogenicity of an eleven valent mixed carrier Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid or tetanus protein conjugate vaccine in Finnish and Israeli infants.  Pediatr Infect Dis J. 2004;23:91-98
PubMed   |  Link to Article
Puumalainen T, Zeta-Capeding MR, Kayhty H.  et al.  Antibody response to an eleven valent diphtheria-and tetanus-conjugated pneumococcal conjugate vaccine in Filipino infants.  Pediatr Infect Dis J. 2002;21:309-314
PubMed   |  Link to Article
Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.  N Engl J Med. 2003;349:1341-1348
PubMed   |  Link to Article
Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus, I: the role of humoral antibodies.  J Exp Med. 1969;129:1307-1326
PubMed   |  Link to Article
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
PubMed   |  Link to Article
Anderson P, Treanor J, Porcelli S, Pichichero M. Non-interference between two protein carriers when used with the same polysaccharide for pneumococcal conjugate vaccines in 2-year-old children.  Vaccine. 2003;21:1554-1559
PubMed   |  Link to Article
Greenberg DP, Wong VK, Partridge S.  et al.  Immunogenicity of a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine when mixed with a diphtheria-tetanus-acellular pertussis-hepatitis B combination vaccine.  Pediatr Infect Dis J. 2000;19:1135-1140
PubMed   |  Link to Article
Barington T, Skettrup M, Juul L, Heilmann C. Non-epitope-specific suppression of the antibody response to Haemophilus influenzae type b conjugate vaccines by preimmunization with vaccine components.  Infect Immun. 1993;61:432-438
PubMed
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
PubMed   |  Link to Article
Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction.  Lancet. 2004;364:365-367
PubMed   |  Link to Article
McVernon J, Maclennan J, Clutterbuck E, Buttery J, Moxon ER. Effect of infant immunisation with meningococcus serogroup C-CRM(197) conjugate vaccine on diphtheria immunity and reactogenicity in pre-school aged children.  Vaccine. 2003;21:2573-2579
PubMed   |  Link to Article
World Health Organization.  Vaccine Research and Development: Report of a Technical Review Group Meeting, June 9-10, 1997Geneva, Switzerland: WHO; 1997:32-36
Cronin WA, Germanson TP, Donowitz LG. Intravascular catheter colonization and related bloodstream infection in critically ill neonates.  Infect Control Hosp Epidemiol. 1990;11:301-308
PubMed   |  Link to Article
Sleeman K, Knox K, George R.  et al.  Invasive pneumococcal disease in England and Wales: vaccination implications.  J Infect Dis. 2001;183:239-246
PubMed   |  Link to Article
Huebner RE, Wasas AD, Klugman KP. Trends in antimicrobial resistance and serotype distribution of blood and cerebrospinal fluid isolates of Streptococcus pneumoniae in South Africa, 1991-1998.  Int J Infect Dis. 2000;4:214-218
PubMed   |  Link to Article

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