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ANTIBODY PERSISTENCE 66 MONTHS AFTER A BOOSTER DOSE OF COMBINED HAEMOPHILUS INFLUENZAE TYPE B–NEISSERIA MENINGITIDIS SEROGROUP C–TETANUS-TOXOID (HIB-MENC-TT) CONJUGATE VACCINE
JUAN C. TEJEDOR,1 JOSÉ MANUEL MERINO,2 MANUEL MORO,3 MARIA-LUISA NAVARRO,4 JOSÉ ESPIN,5 FÉLIX OMEÑACA,6 JOSÉ GARCIA-SICILIA,6 DAVID MORENO-PEREZ,7 JESUS RUIZ-CONTRERAS,8 FERNANDO CENTENO,9 FRANCISCO BARRIO,10 LUCIA CABANILLAS,11 MARTA MURO,11 CARLOS ESPORRIN,12 MARIA JOSE DE TORRES,10 KAVITHA PEDDIRAJU,13 JACQUELINE MILLER,13 NARCISA MESAROS,13
1

Hospital de Móstoles, Móstoles, Spain; 2Hospital General Yagüe, Burgos, Spain; 3Hospital Clinico San Carlos, Madrid, Spain; 4Hospital General Universitario Gregorio Marañón, Madrid, Spain; 5Hospital Torrecardenas, Almeria, Spain; 6Hospital Infantil Universitario La Paz, Madrid, Spain; 7Hospital Carlos Haya, Malaga, Spain; 8Hospital 12 De Octubre, Madrid, Spain; 9Hospital Rio Hortega, Valladolid, Spain; 10Hospital Comarcal De La Axarquia, Malaga, Spain; 11Hospital Universitario de Getafe, Madrid; 12Hospital Santa Caterina, Girona, Spain; 13GSK Biologicals India, Belgium and USA.

BACKGROUND
Invasive diseases caused by Haemophilus in uenzae type b (Hib) and Neisseria meningitidis are major causes of morbidity and mortality in young children worldwide.1,2 Hib and N. meningitidis serogroup C (MenC) conjugate vaccines are effective in preventing these infections in young children as early as 2 months of age.1,3,4,5,6 Menitorix™, a combined Hib and MenC tetanus-toxoid conjugate vaccine (HibMenC-TT), has been demonstrated to be immunogenic when given in a 2, 4, 6 and 12 months-of-age schedule.7,8 In a previous timepoint for this study, persistent Hib and MenC antibodies following 2, 4, 6 and 12 months-of-age vaccination schedule were observed up to 18 months after the booster vaccination.7 Persisting antibodies are more important than immune memory in long-term protection against Hib and MenC diseases.9 Here we present the Hib and MenC long-term antibody persistence up to 66 months after the booster vaccination in children who were vaccinated at 2, 4, 6, and 13–14 months of age.

METHODS Design
This was a phase III, open, multicentre extension study conducted at 12 centres in Spain. Infants were randomised 1:2:1 to receive the following vaccines in the primary (NCT00352963) and booster phases (NCT00323050): o HibMenC group: 3 doses of Hib-MenC-TT (Menitorix™) at 2, 4 and 6 months of age, co-administered with DTPa-HBV-IPV (Infanrix™penta), and Hib-MenC-TT at 13–14 months of age; o Neis_HibMenC group: 2 doses of MenC-TT (NeisVac-C™) at 2 and 4 months of age, co-administered with DTPa/Hib containing vaccines at 2, 4 and 6 months of age, and Hib-MenC-TT at 13–14 months of age; o MenC-CRM group: 3 doses of MenC-CRM197 (Meningitec™) at 2, 4 and 6 months of age co-administered with DTPa-HBV-IPV/Hib (Infanrix™hexa), and boosted with Infanrix™hexa at 13–14 months of age. At the time of the booster study, a booster dose of meningococcal serogroup C vaccine was not recommended in Spain. All subjects in the MenC-CRM group were offered a dose of MenC-CRM197 at the end of the booster vaccination study. Blood samples were taken from each subject 1 month post-primary vaccination, just prior to the booster vaccination, and 1, 18, 30, 42, 54 and 66 months postbooster vaccination. The according-to-protocol (ATP) cohort for antibody persistence at Month 66 included all evaluable subjects who: o received their primary and booster vaccinations according to the randomisation assignment; o had persistence data available for at least one antigen; o had not received Hib or MenC vaccines except the study vaccines, with the exception of the MenC-CRM197 booster offered to subjects in the MenC-CRM group;

Immunogenicity assessment
Anti-polyribosylribitol phosphate (PRP; the Hib polysaccharide) concentrations were measured by enzyme-linked immunosorbent assay (ELISA), with cut-off of ≥0.15 g/mL (accepted correlate of short-term seroprotection10). MenC antibody concentrations were measured by serum bactericidal activity using rabbit complement (rSBA) with a cut-off of ≥1:8 (accepted correlate of protection11).

Safety analyses
Any serious adverse events (SAEs) that occurred since the previous visit, assessed by the investigator as possibly vaccine-related, were retrospectively recorded.

Statistical Analyses
Exploratory analyses evaluated the between-group differences with respect to antibody persistence for the 3 groups: o The difference in percentage of subjects reaching the different cut-offs with their standardised asymptotic 95% con dence intervals (CIs) was assessed. Between group differences were considered signi cant if the 95% CIs did not include the value ‘0’. o The ratio in geometric mean antibody titres (GMTs) and geometric mean antibody concentrations (GMCs) with their standardised asymptotic 95% CIs were computed. Between group ratios were considered signi cant if the 95% CIs did not include the value ‘1’.

RESULTS Demography
Figure 1 shows the ow of subjects through the different phases of the study. One hundred and ninety seven subjects were included in the ATP cohort for persistence at Month 66 post-booster. No subjects discontinued due to safety concerns. Demographic characteristics of the 3 groups are shown in Table 1.

o and did not have a history of Hib or MenC diseases.

Hib immunogenicity
One hundred percent of the subjects in the HibMenC and Neis_HibMenC groups retained anti-PRP antibody levels ≥0.15 µg/mL 66 months after administration of the booster vaccination, as did 97.9% of subjects in the MenC-CRM group (Figure 2a). Exploratory group comparisons suggested higher anti-PRP GMCs in the Neis_HibMenC group compared with the HibMenC group at Month 66 (Figure 2b).

MenC immunogenicity
The percentage of subjects with rSBA-MenC antibody titres ≥1:8 at Month 66 was 82.6% in the HibMenC group, 94.1% in the Neis_HibMenC group and 60.9% in the MenC-CRM group (Figure 3a). At Month 66, the exploratory group comparisons suggested higher rSBA-MenC titres ≥1:8 and GMTs in the HibMenC and Neis_HibMenC groups compared with the MenC-CRM group, and higher rSBA-MenC titres ≥1:8 in the Neis_HibMenC group compared with the HibMenC group (Figure 3b).

Figure 1. Study ow – primary, booster and long-term follow-up phases

Figure 2a. Percentage of subjects with anti-PRP concentrations ≥0.15 µg/mL (ATP cohort for persistence at Month 66)

Figure 3a. Percentage of subjects with rSBA-MenC titres ≥1:8 (ATP cohort for persistence at Month 66)

*

Reasons for exclusion from the ATP cohort for persistence were: randomisation failure, administration of vaccines/medication forbidden by the protocol, and essential serological data missing. No subjects were withdrawn due to adverse events. The subject numbers at each timepoint are those in the ATP Cohort for Persistence at Month 66 with data available at that timepoint. b At the time of the study, Spain did not recommend a booster dose of MenC vaccine. When the immunisation schedule was modi ed, subjects were offered a dose of Meningitec™, at 14–15 months of age. These subjects were excluded from the ATP cohort for persistence at M18. Subjects who received a fourth dose of Meningitec™ were invited to enter the long-term persistence study at M30. ATP = according-to-protocol
a

* At Month 66, the percentage of subjects in the Neis_HibMenC and HibMenC groups with rSBA-MenC titres ≥1:8 was statistically signi cantly higher than in the MenC-CRM group.

Figure 2b. Geometric mean anti-PRP antibody concentrations (ATP cohort for persistence at Month 66)

Figure 3b. Geometric mean rSBA-MenC titres (ATP cohort for persistence at Month 66)

** * *

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Table 1. Demographics (ATP cohort for persistence at Month 66)

HibMenC (N=47)

Neis_HibMenC (N=103)

MenC-CRM (N=47)

Mean age, months (SD) Female, n (%) Caucasian, n (%)

79.2 (0.78) 21 (44.7) 39 (83)

79.1 (0.85) 45 (43.7) 97 (94.2)

79.3 (0.98) 24 (51.1) 44 (93.6)

Safety
No SAEs considered by the investigator to have a possible relationship to vaccination were reported between the booster vaccination and the Month 66 assessment.
* At Month 66, the GMCs in the Neis_HibMenC group were statistically signi cantly higher than in the HibMenC group. * At Month 66, the GMTs were statistically signi cantly higher in the Neis_HibMenC and HibMenC groups compared with the MenC-CRM group. ** The Neis_HibMenC GMTs were also statistically signi cantly higher than in the HibMenC group (Month 66).

REFERENCES
1. Kelly DF, et al. Immunology 2004; 113: 163–74. 2. Harrison LH, et al. Vaccine 2009; 27S: B51–63. 3. Pollard AJ. Pediatr Infect Dis J 2004; 23: S274–9. 4. Trotter CL, et al. Lancet 2004; 364: 365–7. 5. Campbell H, et al. Clin Vaccine Immunol 2010; 17: 840–7. 6. MacNeil JR, et al. Pediatr Infect Dis J 2011; 30: 451–5. 7. Tejedor JC, et al. Ped Infect Dis J 2008; 27: 579–88. 8. Tejedor JC, et al. Ped Infect Dis J 2007; 26: 1–7. 9. Auckland C, et al. JID 2006; 194: 1745–52. 10. Käyhty H, et al. J. Infect. Dis 1983; 147: 1100. 11. Borrow R, et al. Vaccine 2005; 23: 2222–7. Menitorix™, Infanrix™ penta and Infanrix™ hexa are trademarks of GlaxoSmithKline Biologicals, Rixensart, Belgium NeisVac-C™ is a trademark of Baxter Healthcare SA, Zurich, Switzerland Meningitec™ is a trademark of P zer Inc., New York, NY, USA

At the time of the study Spain did not recommend a booster dose of MenC vaccine; post-booster data for this time point are not therefore available. When the immunisation schedule was modi ed, subjects were offered a dose of Meningitec™ at 14–15 months of age. These subjects were excluded from the ATP cohort for persistence at M18. Subjects who received a fourth dose of Meningitec™ were invited to enter the long-term persistence study at M30. ATP = according-to-protocol, HibMenC = primed with Hib-MenC-TT + DTPa-HBV-IPV, boosted with Hib-MenC-TT, Neis_HibMenC = primed with MenC-TT and a DTPa/Hib-containing vaccine, boosted with Hib-MenC-TT; MenCCRM = primed with MenC-CRM197 + DTPa-HBV-IPV/Hib, boosted with MenC-CRM197 + DTPa-HBV-IPV/Hib; PP = Post-primary vaccination (Post-dose 3 for HibMenC and MenC-CRM groups; Post-dose 2 for Neis_HibMenC group); PreB = just prior to booster dose; PostB = Post-booster dose (Month 1); M18 = Post-booster dose (Month 18); M30 = Post-booster dose (Month 30); M42 = Post-booster dose (Month 42); M54 = Post-booster dose (Month 54); M66 = Post-booster dose (Month 66)

DISCUSSION AND CONCLUSION
Protective anti-PRP antibody concentrations persisted in 100% of children in HibMenC and Neis_HibMenC groups and 97.9% of children in MenC-CRM group up to 66 months following the booster vaccination. More than 82% of children boosted with Hib-MenC-TT and 60% of children primed and boosted with MenC-CRM197 retained seroprotective rSBA-MenC antibodies. The sharpest decrease in the anti-PRP antibody concentration and rSBA-MenC titres was observed in the rst 18 months post-booster vaccination, after which levels remained relatively constant up to 66 months post-booster. One booster dose of Hib-MenC-TT given to toddlers after a Hib-MenC-TT or MenC-TT priming course resulted in persisting antibodies up to 66 months post-booster in the majority of subjects, regardless of the priming schedule used.

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Corresponding author: José Manuel Merino jmmerino@hgy.es

ESPID 2012, 30th Annual Meeting of the European Society for Paediatric Infectious Diseases, Thessaloniki, Greece, May 8–12, 2012

NCT00322335