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Clinical and Vaccine Immunology, April 2007, p. 426-434, Vol. 14, No. 4
1071-412X/07/$08.00+0     doi:10.1128/CVI.00377-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Immunogenicity, Reactogenicity, and Immune Memory after Primary Vaccination with a Novel Haemophilus influenzae-Neisseria meningitidis Serogroup C Conjugate Vaccine{triangledown}

Heinz-J. Schmitt,1 Gudrun Maechler,2,{dagger} Pirmin Habermehl,1 Markus Knuf,1 Roland Saenger,3,{ddagger} Norman Begg,2 and Dominique Boutriau2*

Johannes-Gutenberg-Universität, Langenbeckstr. 1, 55101 Mainz,1 GlaxoSmithKline, Munich, Germany,3 GlaxoSmithKline Biologicals, Rixensart, Belgium2

Received 10 October 2006/ Returned for modification 16 November 2006/ Accepted 29 January 2007


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ABSTRACT
 
We evaluated two formulations of a new combined Haemophilus influenzae type b (Hib)-meningococcal serogroup C (MenC)-tetanus toxoid (TT) conjugated vaccine and two formulations of a new MenC-TT vaccine (trials 711202/001 and 711202/008; clinical trial register numbers NCT00135486 and NCT00135564 [www.ClinicalTrials.gov]). A total of 520 healthy infants were randomized to receive primary vaccination (at 2, 3, and 4 months) with either MenC-TT plus diphtheria-tetanus-acellular pertussis (DTPa)-hepatitis B virus (HBV)-inactivated poliovirus (IPV)/Hib, Hib-MenC-TT plus DTPa-HBV-IPV, or MenC-CRM197 plus DTPa-HBV-IPV/Hib (control). At 12 to 15 months, subjects received a polysaccharide challenge with meningococcal polysaccharide C plus a DTPa-HBV-IPV/Hib booster. Immune responses were assessed 1 month after dose 2, 1 month after dose 3, and prior to and 1 month after the booster. After primary vaccination, there was no difference between groups in seroprotection rates as measured by titers of serum bactericidal antibody (SBA) to MenC (≥1:8) or concentrations of anti-polyribosyl ribitol phosphate (PRP) antibody (≥0.15 µg/ml). Prior to the booster, there was no difference between groups in SBA seroprotection rates, whereas anti-PRP seroprotection rates were significantly higher after priming with Hib-MenC-TT. Booster doses induced large increases in SBA and anti-PRP antibodies in primed groups, indicating successful priming with induction of immune memory. Reactogenicity and safety were similar in all groups during the primary and booster phases. A novel combined Hib-MenC-TT conjugate vaccine induced MenC and Hib responses comparable to those induced by licensed monovalent vaccines. A Hib-MenC-TT conjugate vaccine provides vaccination against two major pathogens in a single injection and is a suitable candidate for use in primary or booster vaccination schedules.


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INTRODUCTION
 
Historically, Haemophilus influenzae type b (Hib), Neisseria meningitidis, and Streptococcus pneumoniae have been responsible for the vast majority of occurrences of bacterial meningitis in children <5 years old. The introduction of Hib conjugate vaccines during the 1990s fundamentally altered the epidemiology of Hib disease. The availability of effective conjugate vaccines against S. pneumoniae, Hib, and N. meningitidis serogroup C raises the possibility that invasive disease due to these three organisms may be virtually eliminated in young children.

Before the introduction of meningococcal serogroup C (MenC) conjugate vaccination, serogroups B and C were the two most common causes of meningococcal disease in developed countries, including Europe, Australia, and the Americas (1, 4, 12, 17). The burden of endemic disease is highest in infants and children <5 years old (1, 12). In Europe during 1999 to 2000, 16% of cases occurred in children <1 year old (38.6/100,000), and 43% in children <5 years old (14.4/100,000) (12). Increasing case numbers due to serogroup C have been observed in the United Kingdom, Spain, Belgium, Ireland, The Netherlands, and Greece (7, 11, 24). In 1999, a mass vaccination campaign with the first MenC conjugate vaccines was launched in the United Kingdom, aiming to protect the whole population below the age of 25 years. The vaccine was also introduced into the routine infant immunization schedule. An overall reduction in disease of 81% was observed (10).

A novel Hib-MenC-tetanus toxoid (TT) vaccine (containing 5 µg of Hib antigen and 5 µg of MenC antigen) was recently licensed in the United Kingdom (Menitorix; GlaxoSmithKline [GSK] Biologicals). This study evaluated the immunogenicity and safety of the new Hib-MenC-TT vaccine, as well as those of a MenC-TT vaccine, when administered for primary vaccination at the ages of 2, 3, and 4 months. Persistence and immune memory were also assessed.

(The results of these studies have been presented in part at the 4th World Congress of the World Society for Pediatric Infectious Diseases, 1 to 4 September 2005, Warsaw, Poland.)


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MATERIALS AND METHODS
 
Study design and subjects. An open, randomized multicenter study was conducted at 55 sites in Germany. The study protocol was approved by the ethics review committees of the study centers, and the study was conducted according to the ICH Good Clinical Practice guideline, German drug acts, and the Declaration of Helsinki. Written informed consent was obtained from the parents/guardians of each subject at each phase of the study.

In the primary phase, eligible infants were randomized to one of five parallel groups: (i) group MenC, receiving a vaccine containing 10 µg of MenC antigen plus diphtheria-tetanus-acellular pertussis (DTPa)-hepatitis B virus (HBV)-inactivated poliovirus (IPV)/Hib; (ii) group MenCads, receiving a vaccine containing 10 µg of MenC antigen adsorbed onto aluminum plus DTPa-HBV-IPV/Hib; (iii) group Hib10-MenC10, receiving a vaccine containing 10 µg of Hib antigen and 10 µg of MenC antigen plus DTPa-HBV-IPV; (iv) group Hib5-MenC5, receiving a vaccine containing 5 µg of Hib antigen and 5 µg of MenC antigen plus DTPa-HBV-IPV; and (v) the control group, receiving MenC-CRM197 (Meningitec) plus DTPa-HBV-IPV/Hib (Infanrix hexa) (Fig. 1). Primary vaccination was administered at the ages of 2, 3, and 4 months.


Figure 1
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  		FIG. 1. Vaccination schedule. Blood samples were collected before the first primary vaccine dose, 1 month after the second primary vaccine dose, 1 month after the third primary vaccine dose, and before and 1 month after the booster dose.

All groups except group MenCads were included in the booster phase. Subjects from group MenCads were offered a dose of a licensed MenC conjugate vaccine in the second year of life. An additional group, "group O," was added to the booster phase; it consisted of age-matched MenC-naïve subjects vaccinated according to the German vaccination schedule (9). At the age of 12 to 15 months, all subjects received one-fifth dose of Men ACWY vaccine (Mencevax, an N. meningitidis polysaccharide vaccine containing serogroups A, C, W135, and Y) concomitantly with DTPa-HBV-IPV/Hib.

Healthy infants between the ages of 8 and 16 weeks at the time of first vaccination were eligible for inclusion in the study. Subjects were excluded in case of major congenital defects or serious chronic illness; immunodeficiency; previous/intercurrent vaccination or disease with study vaccine antigens; allergy to any component of the vaccine; use or planned use of other investigational or nonregistered drugs/vaccines; receipt of blood products including immunoglobulin before or during the trial; neurologic disorders or seizures; or acute disease at the time of enrollment.

Vaccines. All vaccines used were developed and manufactured by GSK (Rixensart, Belgium), except for MenC-CRM197 (Meningitec), developed and manufactured by Wyeth Vaccines (Pearl River, NY). The MenC-TT vaccines contained 10 µg N. meningitidis polysaccharide C (PSC) conjugated to TT. The MenCads vaccine was adsorbed onto aluminum hydroxide. Two formulations of the combined Hib-MenC-TT vaccine were evaluated: Hib10-MenC10 contained 10 µg polyribosyl ribitol phosphate (PRP) and 10 µg PSC conjugated to TT, and Hib5-MenC5 contained 5 µg each of PRP and PSC conjugated to TT (Menitorix). The composition of DTPa-HBV-IPV/Hib (Infanrix hexa) and that of DTPa-HBV-IPV (Infanrix penta) have been described elsewhere (22). MenC-CRM197 contains 10 µg PSC conjugated to Corynebacterium diphtheriae CRM197 protein, absorbed onto aluminum. Men ACWY (Mencevax) contains 50 µg each of purified polysaccharides from N. meningitidis serogroups A, C, W135, and Y.

(Meningitec is a trademark of Wyeth; Menitorix, Infanrix hexa, Infanrix penta, and Mencevax are trademarks of the GSK group of companies.)

All novel formulations were supplied as lyophilized pellets in monodose vials and were reconstituted with saline. The DTPa-HBV-IPV, DTPa-HBV-IPV/Hib, and MenC-CRM197 vaccines were prepared according to the manufacturers' instructions. One dose of the lyophilized Men ACWY vaccine was reconstituted with 1.0 ml diluent, and 0.2 ml (one-fifth dose, equal to 10 µg each of serogroup A, C, W135, and Y polysaccharides) was administered as a separate injection during the booster phase. All vaccines were administered intramuscularly in the thigh.

Assessment of antibody response. Blood samples were collected before primary vaccination (month zero), 1 month after dose 2 (month 2), 1 month after dose 3 (month 3), and prior to and 1 month after the booster dose in the second year of life. Sera were stored at –20°C until blinded analysis at GSK, Rixensart, Belgium. The immune responses to MenC, Hib, and tetanus toxoid were measured at each time point, while the immune responses to diphtheria toxoid, pertussis, polio, and hepatitis B antigens were measured at month zero and month 3 only.

Serum bactericidal antibodies to MenC (SBA-MenC) were measured by a serum bactericidal test using baby rabbit complement and the C11 strain (9). The cutoff of the test was a dilution of 1:8, which is considered to be protective (2). Different methodologies were used for the SBA-MenC assay during the primary and booster phases: in the primary phase, titers were expressed as discrete twofold-dilution values, while in the booster phase, titers were expressed as continuous values (obtained via curve fitting to derive the exact theoretical dilution giving 50% bactericidal activity), in order to improve the reproducibility of the assay. Therefore, no comparison should be made between the post-primary vaccination and the pre- and post-booster vaccination time points. Antibodies against PSC were measured by an enzyme-linked immunosorbent assay (ELISA) (13). The assay cutoff was 0.3 µg/ml.

Antibodies against PRP, diphtheria and tetanus toxoids, pertussis antigens (pertussis toxin [PT], filamentous hemagglutinin [FHA], and pertactin [PRN]), and hepatitis B surface antigen (HBs) were determined by ELISA, as previously described (3). The cutoff values for the assays were 0.15 µg/ml for anti-PRP; 0.1 IU/ml for diphtheria and tetanus toxoid antibodies; 5 ELISA units/ml for PT, FHA, and PRN; and 10 mIU/ml for anti-HBs.

For SBA-MenC, PRP, diphtheria, tetanus, HBs and polio, an antibody level greater than or equal to the assay cutoff was considered to be protective. For SBA-MenC, an antibody level greater than or equal to the assay cutoff was considered to be seropositive. For pertussis, a vaccine response was defined as a postvaccination antibody concentration greater than or equal to the assay cutoff value for initially seronegative infants and as a postvaccination concentration greater than or equal to the prevaccination concentration for initially seropositive infants (thereby taking into account the half-life of maternal antibodies).

Assessment of safety. Solicited local adverse reactions (pain, redness, swelling) and solicited general symptoms (fever [defined as a rectal body temperature of ≥38.0°C], irritability/fussiness, drowsiness, loss of appetite) were recorded by completing diary cards for 8 days after each primary vaccination and for 4 days following the booster dose. All other symptoms, serious adverse events (SAEs), and extensive injection site swellings were recorded during the entire study period until 30 days following the last vaccination. Symptom intensity was scored on a 4-point scale. Symptoms of grade 3 intensity were defined as follows: for pain, crying when the limb is moved/spontaneously painful (i.e., pain when the limb is moved and when it is stationary); for redness and swelling, a diameter of >30 mm; for fever, a temperature of >40.0°C; for all other adverse events, prevention of everyday activities and causing the parents/guardians to seek medical advice. The parents/guardians were asked to contact the investigator immediately if the child manifested any signs that were perceived as serious.

Statistical methods. Geometric mean antibody concentrations/titers (GMC/T) with 95% confidence intervals (CIs) were calculated, and antibody concentrations/titers below the assay cutoff were given an arbitrary value of half the cutoff value for the purpose of GMC/T calculation. Seropositivity/seroprotection/vaccine response rates with exact 95% CIs were calculated.

After primary vaccination, exploratory comparisons between groups were performed through computation of standardized asymptotic 95% CIs for the difference in seroprotection/seropositivity/vaccine response rates between each of the study vaccine groups and the control group. Additionally, 95% CIs for the GMC/T ratios between groups were determined using a one-way analysis of variance model on the log10 transformation of titers.

After the polysaccharide challenge, an exploratory comparison of the experimental formulations and the MenC-naïve group O was performed in terms of the SBA-MenC and PSC responses through computation of 95% CIs for the GMC/T ratios between groups. Using the same method, the differences between the three experimental groups and the control group in terms of the anti-PRP and anti-tetanus immune responses after the booster dose of DTPa-HBV-IPV/Hib were also computed.

Two vaccine groups were considered significantly different if the standardized asymptotic 95% CI for the difference in seroprotection/seropositivity/vaccine response rates between the two groups did not contain a value equivalent to 0. For GMC/T, groups were considered significantly different if the 95% CI for the GMC/T ratio between groups did not contain a value equivalent to 1. When exploratory analyses were not performed, differences were evaluated by considering the overlap of 95% CIs. The risk of error due to the multiplicity of comparisons was not adjusted.

The incidence and intensity of each solicited adverse event were tabulated with the exact 95% CI. A sample size of 500 subjects to provide 80 evaluable subjects per group for the immunogenicity analysis provided 92% individual power for each of the four comparisons to be done to rule out the null hypothesis: the SBA-MenC seroprotection rate for a MenC group was >10% lower than that for the control group receiving MenC-CRM197 (expected proportions, 95% in group MenC and 98% in the control group; nQuery alpha = 0.025).


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RESULTS
 
A total of 520 healthy infants were enrolled in the primary vaccination phase during 2003 (Fig. 2). A total of 483, 448, and 418 subjects contributed to the primary analyses for immunogenicity in the primary, persistence, and booster phases, respectively.


Figure 2
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  		FIG. 2. Subjects enrolled and reasons for elimination from analyzed cohorts.

The mean age of subjects at the time of the first dose was 11.3 weeks (range, 8 to 16 weeks); 49.7% were male, and 96.3% were Caucasian. Of 416 subjects in the four primary vaccination groups eligible for inclusion in the booster phase, 363 (87%) were enrolled, and an additional 96 age-matched controls were also enrolled. The mean age at the time of the booster was 12.8 months (range, 12 to 15 months), and 53.8% of subjects were male. Demographic characteristics were similar between groups (data not shown).

Of 10 subjects who dropped out of the primary vaccination phase before completion (Fig. 2), 3 did so due to adverse events: the onset of pertussis 11 days after dose 1 (group MenCads), thrombocytopenia 11 days after dose 2 (control group), and the onset of current fever 29 days after dose 2 (control group). All three events resolved without sequelae, and none were considered by the investigator to be related to vaccination. No dropouts due to adverse events were observed during the booster phase.

Immunogenicity. (i) Primary vaccination phase. More than 95% of subjects had seroprotective SBA-MenC antibody titers (≥1:8) 1 month after dose 2, and at least 98% had them 1 month after dose 3 (Table 1). Hib5-MenC5 vaccines induced seroprotective levels in all subjects after dose 2. One month after dose 3, at least 96.6% of subjects in all groups, except group MenCads (90.9%), achieved SBA-MenC titers of ≥1:128 (data not shown). There was no statistical difference among experimental and control groups in the proportion of subjects reaching the 1:8 or 1:128 cutoffs at either month 2 or month 3, except for group MenCads, where significantly fewer subjects than in the control group achieved titers of ≥1:128 at month 3. GMTs were statistically lower for each study vaccine group than for the control group at both time points, with the lowest GMT observed for group MenCads.


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  		TABLE 1. SBA-MenC, PSC, and PRP immune responses 1 month after primary vaccination

One hundred percent of subjects achieved anti-PSC antibody concentrations of ≥0.3 µg/ml by month 2 (Table 1). Anti-PSC GMCs did not differ statistically between groups at month 2, whereas at month 3, statistically low GMCs were observed for all groups compared to the control, except group MenC.

After primary vaccination, anti-PRP antibody seroprotection levels were high in all groups (>97%), but the proportion of subjects with antibody levels of ≥1.0 µg/ml was significantly higher in the Hib5-MenC5 and Hib10-MenC10 groups than in the control group (95.6% and 98.9% versus 80.0% for groups Hib10-MenC10 and Hib5-MenC5 versus the control group, respectively). Significantly higher anti-PRP antibody GMCs were observed in all experimental groups than in the control group; anti-PRP antibody GMCs were highest in both groups vaccinated with a Hib-MenC combination.

There were no statistically significant differences between groups in terms of diphtheria, tetanus, hepatitis B, pertussis, and poliovirus antibody seropositivity/seroprotection/vaccine response rates (Table 2) at month 3. Antibody GMC/T for all component antigens were of similar orders in all groups, with the exception of diphtheria and tetanus: anti-diphtheria antibody GMCs were significantly higher in the control group, and anti-tetanus GMCs were significantly higher in all four experimental vaccine groups.


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  		TABLE 2. HBs, diphtheria, tetanus, polio, and pertussis immune responses 1 month after primary vaccination

(ii) Antibody persistence and booster phase. Based on the results of the primary vaccination phase, development of the experimental MenCads vaccine was discontinued, and this group was not evaluated further.

Prior to the booster dose, there was no difference between experimental or control groups in the proportion of subjects with SBA-MenC antibody titers of ≥1:8 (Table 3). In contrast to the post-primary vaccination findings, prebooster SBA-MenC GMTs tended to be higher for group Hib5-MenC5 than for the control group and were statistically significantly higher for group MenC. Most subjects were still seropositive for anti-PSC antibody as measured by ELISA, with no difference between groups. Anti-PSC antibody GMCs were significantly lower for groups Hib10-MenC10 and Hib5-MenC5 than for the control group. Prior to the booster doses, anti-PRP antibody seroprotection rates and GMCs were both significantly higher for groups Hib10-MenC10 and Hib5-MenC5 than for the control group. Anti-tetanus seroprotection rates were not significantly different between groups prior to the booster dose; however, anti-tetanus antibody GMCs continued to be higher for all of the experimental vaccine groups than for the control group (data not shown).


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  		TABLE 3. SBA-MenC, PSC, and PRP antibody persistence (prebooster) and immune response 1 month after polysaccharide challenge and DTPa-HBV-IPV/Hib booster doses (postbooster)

The administration of a 10-µg challenge dose of plain PSC elicited a marked booster response in all four groups that had received primary vaccination with a MenC conjugate vaccine (Table 3). The response is in striking contrast to that of MenC-naïve subjects in group O: more than 90% of subjects primed with a MenC conjugate vaccine had SBA-MenC titers of ≥1:128 after the polysaccharide challenge, compared with 17.6% in group O. Postchallenge GMTs were significantly higher for groups MenC and Hib5-MenC5 than for the control group.

Similarly, polysaccharide challenge induced increases in anti-PSC antibody levels of at least eightfold for the experimental groups, higher than those for the control group. Notably, 95.7% of unprimed subjects responded to the challenge dose with anti-PSC concentrations of ≥0.3 µg/ml but with lower GMCs.

All subjects received a booster dose of DTPa-HBV-IPV/Hib on the same day as the polysaccharide challenge. One month later, at least 98.8% of subjects had anti-PRP antibody concentrations of ≥0.15 µg/ml and at least 96.5% of subjects had concentrations of ≥1.0 µg/ml. Statistically significantly higher anti-PRP GMCs were observed for the group primed with Hib5-MenC5 than for the control group.

One month after the booster dose, all subjects in all five groups had seroprotective concentrations of anti-tetanus antibodies. Anti-tetanus antibody GMCs continued to be significantly higher for all three experimental vaccine groups than for the control group.

Safety. Redness and drowsiness/irritability were the most commonly reported local and general solicited symptoms, respectively, after primary vaccination (Fig. 3 and 4). Symptoms of grade 3 intensity occurred infrequently. Incidences of reported local and general solicited symptoms were within the same range for the different treatment groups. After the booster dose, the incidences of local symptoms of pain, redness, and swelling were higher than those after primary vaccination. Reported general solicited symptoms increased to a lesser degree after the booster dose. No difference in the incidence of local or general symptoms after the booster was observed between groups, including the group that had not previously received primary vaccination with a MenC-containing vaccine (group O).


Figure 3
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  		FIG. 3. Incidence of solicited local and general symptoms, with 95% CIs, within the 8-day follow-up period after primary vaccination. Results are shown for all primary doses combined, for the MenC or Hib-MenC injection site, and for the total cohort receiving primary vaccination.


Figure 4
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  		FIG. 4. Incidence of solicited local and general symptoms, with 95% CIs, within the 4-day follow-up period after booster vaccination. Local symptoms occurred at the Infanrix hexa injection site. Results are shown for the total cohort receiving the booster vaccination. Infanrix hexa plus one-fifth dose of Mencevax (Men ACWY) was given as a booster to all subjects.

During primary vaccination, a total of 13 SAEs were reported for 12 subjects (4 in group MenC, 3 in group MenCads, 2 in group Hib10-MenC10, 1 in group Hib5-MenC5, and 2 in the control group): bronchitis, pyelonephritis (3 cases), degenerative brain disease with epilepsy, skull fracture, coordination disturbance, pertussis, apnea, otitis media, thrombocytopenia, pneumonia, and vomiting. None were considered by the investigator to be vaccine related. No deaths were reported. Four SAEs occurred during the booster phase (two in group MenC, one in group Hib10-MenC10, and one in the control group): pseudocroup, viral infection, bronchitis, and febrile convulsion. None were determined by the investigator to be causally related to vaccination.


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DISCUSSION
 
This study has demonstrated the feasibility of a novel combined Hib-MenC conjugate vaccine for the primary vaccination of infants. The reduced-content Hib5-MenC5 vaccine was highly immunogenic and induced immune memory following primary vaccination. High levels of SBA-MenC seroprotection and anti-PSC seropositivity after two doses of the experimental MenC or Hib-MenC vaccines, similar to levels observed after dose 3 in the control group, were observed. A polysaccharide challenge in the second year of life induced very large increases in antibody concentrations and bactericidal titers. Anti-PSC antibody levels were significantly higher in groups that had received primary vaccination with a combined Hib-MenC vaccine, and SBA-MenC titers were significantly higher in the group that had received reduced polysaccharide levels during primary vaccination (Hib5-MenC5). The greater magnitude of the response to challenge for subjects primed with Hib5-MenC5 is consistent with previous observations, where a lower quantity of antigen given during primary vaccination induced a higher immune memory response (15, 20). We observed that the proportions of subjects who remained seroprotected/seropositive for SBA-MenC and PSC prior to the challenge were not different for the Hib-MenC and control groups, suggesting that the lower SBA-MenC GMT and the lower anti-PSC GMC observed after primary vaccination were of no clinical importance.

To our knowledge, this is the first study where a Hib vaccine containing a reduced quantity of PRP-TT has been coadministered with an acellular pertussis vaccine and the first in which a Hib-MenC conjugate combination vaccine was evaluated. All groups that received primary vaccination with the experimental MenC or Hib-MenC vaccines demonstrated immune responses that were superior compared to those of the control group in terms of anti-PRP antibody GMCs after primary vaccination, with anti-PRP GMCs similar to those observed after vaccination with licensed monovalent Hib conjugate vaccines (18). The Hib-MenC vaccines showed higher anti-PRP seroprotection rates after two doses and higher seroprotection rates 1 year later, at the time of the booster dose. The effect was most marked for the Hib5-MenC5 vaccine, where the high level of immune response observed after two doses was similar to that after three doses of DTPa-HBV-IPV/Hib.

Our results are consistent with previous observations highlighting the complex interactions between conjugated vaccines and DTPa-based vaccines, whereby concomitant administration of MenC-TT with DTPa and Hib-TT vaccines induced a lower SBA-MenC GMT, whereas the same combination of vaccines induced a higher anti-PRP antibody response, although no impact on seroprotection rates was observed (8). Meningitec (using a CRM197 carrier) was chosen as the control vaccine in this study, because it was the first conjugate vaccine licensed in the United Kingdom and was the most frequently used for infant vaccinations and for the beginning of the vaccination campaigns.

The immune memory response was highest in the group primed with Hib5-MenC5. Two factors may explain the observed response: (i) a lower quantity of antigen during primary vaccination may trigger a higher antibody response postchallenge, as reported previously in references 6 and 15, and (ii) the TT carrier may induce a better memory response. Such an effect was also shown when immune memory was evaluated for United Kingdom toddlers primed with one dose of MenC-TT or MenC-CRM197 conjugate at the age of 12 to 18 months (16).

In light of recent experiences with Hib vaccines, where the importance of a booster dose has been demonstrated, particularly when immunologically challenging immunization schedules are employed (5, 14, 20), there has been debate over the need for a booster dose of MenC vaccine after primary vaccination. Recent data from the United Kingdom indicate that infants vaccinated with MenC conjugates at the ages of 2, 3, and 4 months in the routine infant immunization program were not protected for more than a year after the last dose (23) and that seroprotection rates had dropped to low levels in older children who had received vaccination with a single dose (19). Booster vaccination against Hib and MenC during the second year of life is likely to be needed to reinforce and prolong protection after primary vaccination (19, 20).

The new MenC and Hib-MenC study vaccines were coadministered with licensed DTPa-based combination vaccines without impact on the reactogenicity or safety profile compared to that for the control group. The incidences of reported solicited local and general symptoms were similar for subjects primed with a MenC vaccine and subjects who had not received primary vaccination with a MenC vaccine, suggesting that the three-dose primary vaccination course with additional TT present in the new vaccines had no impact on the reactogenicity of the booster dose. Furthermore, there was no evidence to suggest that the high-persisting anti-tetanus and anti-PRP antibody concentrations prior to the booster dose had any impact on the reactogenicity of the DTPa-HBV-IPV/Hib booster.

This new Hib-MenC combined vaccine with reduced amounts of PRP and PSC provides vaccination against two antigens in one injection and may be used for primary or booster vaccination. It may be safely coadministered with the pentavalent DTPa-HBV-IPV vaccine without affecting the immune response of either vaccine; therefore, it may also provide a valid alternative to DTPa-Hib combinations. A high response to both the MenC and Hib components was seen already after the second dose and confirmed in another study (21), suggesting a potential two-dose primary vaccination regime with a booster dose in the second year of life. MenC is now recommended as a two-dose vaccine in most countries recommending infant vaccination.


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ACKNOWLEDGMENTS
 
These studies were funded by GSK Biologicals (studies 711202/001 and 711202/008; clinical trial register numbers NCT00135486 and NCT00135564 [www.ClinicalTrials.gov]). N. Begg, D. Boutriau, G. Maechler, and R. Saenger are employees of the GSK group of companies. In addition, N. Begg and D. Boutriau have stock ownership, and D. Boutriau is an inventor of patent applications. P. Habermehl and M. Knuf declare that they have received honoraria/payment for expert testimony/travel grants from the commercial entity that sponsored the study, and H.-J. Schmitt declares that he has received consulting fees in the past 3 years.

We thank the families who participated in the study, the study investigational team in Germany (C. Witterman, E. Dietmair, B. Castell-Rüdenhausen, H. Preidel, S. Habash, Z. Kollaschinsk, P. K. Gildberg, K. Rosemann, J. Häfelein, H. Johannsen, S. Mohns-Petersen, H. Outzen, B. Pfaffenrath-Schulte, E. M. Schafmeister, R. Schult, H. Krause, R. Holtorf, H.-P. Loch, B. M. Kniese, D. Herrmann, H. Berwanger, W. Otto, S. Nolte, K. H. Walther, K. H. Laakmann, E. Schmitz-Hauss, H. F. Hüsgen, H. Pankow-Culot, P. Soemantri, K. H. Krause, J. Banz, L. Seitz, S. Strauch, F. P. Drobnitzky, D. Richter, S. Milde, F. Bertholdt, U. Henke, K. Kindler, C. Sievers, A. Maurer, M. J. Matting-Köhler, M. Damme, S. Scharfe, H. Bolze-Knothe, K. Weber, R. Freund, C. Möllering, U. Sträubler, M. Nahlik, G. Schumann, T. Müller, and S. Peter), V. Marichal for study coordination, J. Poolman and I. De Vleeschauwer for serological analysis, C. Durand for statistical support, J. Wolter for writing assistance in preparation of the manuscript, L. Rouxhet and Erik Michels for publication coordination, and the study nurses and other staff members, without whom this study would not have been possible.


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FOOTNOTES
 
* Corresponding author. Mailing address: GlaxoSmithKline Biologicals, Rue du l'Institut, 89, 1330 Rixensart, Belgium. Phone: 32-2-656-9120. Fax: 32-2-656-8044. E-mail: Dominique.Boutriau{at}gskbio.com Back

{triangledown} Published ahead of print on 7 February 2007. Back

{dagger} Present address: GlaxoSmithKline, Munich, Germany. Back

{ddagger} Present address: GlaxoSmithKline Biologicals, Rixensart, Belgium. Back


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Clinical and Vaccine Immunology, April 2007, p. 426-434, Vol. 14, No. 4
1071-412X/07/$08.00+0     doi:10.1128/CVI.00377-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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