Downloaded from on May 23, 2020 by guest · 4/28/2016 · 36 influenzae protein D conjugate vaccine [ PHiD -CV] or 7 -valent CRM 197 conjugate vaccine 37 [7vCRM ]). MenC antibody

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Antibody Persistence in Young Children 5 Years after Vaccination with Combined 1

Haemophilus influenzae type b-Neisseria meningitidis Serogroup C or MenC Conjugate 2

Vaccines Co-Administered with DTPa-Containing and Pneumococcal Conjugate 3

Vaccines 4

5

Juan Carlos Tejedor,a Jerzy Brzostek,

b Ryszard Konior,

c Detlef Grunert,

d Devayani Kolhe,

e 6

Yaela Bainef and Marie Van Der Wielen

g# 7

8

Unidad Neonatal, Hospital Universitario de Móstoles, Madrid, Spaina; Pediatrics Department, 9

Zespol Opieki Zdrowotnej w Debicy, Debica, Polandb; Neuro-infection and Pediatric 10

Neurology, John Paul II Hospital, Cracow, Polandc; Praxis, Nordlingen, Germany

d; GSK 11

Vaccines, Bangalore, Indiae; GSK Vaccines, King of Prussia, PA, United States of America

f; 12

GSK Vaccines, Wavre, Belgiumg 13

14

Running head: Antibody persistence to Hib-MenC-TT 15

16

#Address correspondence to Marie Van Der Wielen, MD, GSK Vaccines, Avenue Fleming 17

20, B-1300 Wavre, Belgium. E-mail: [email protected]. Tel: +32 10 85 18

9384. 19

20

Keywords: Haemophilus influenzae type b, Neisseria meningitidis serogroup C, antibody 21

persistence, MenC conjugate vaccine 22

23

24

25

CVI Accepted Manuscript Posted Online 4 May 2016Clin. Vaccine Immunol. doi:10.1128/CVI.00057-16Copyright © 2016 Tejedor et al.This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Abstract 26

Background and aims: We evaluated antibody persistence in children up to 5 years after 27

administration of a combined Haemophilus influenzae type b (Hib)-Neisseria meningitidis 28

serogroup C (MenC) tetanus toxoid conjugate vaccine (Hib-MenC-TT) co-administered with 29

a pneumococcal conjugate vaccine (NCT00891176). 30

Method: This is the follow-up of a randomised study (NCT00334334/00463437), in which 31

healthy children were vaccinated (primary, 2–4–6 months of age; and booster, 11–18 months) 32

with Hib-MenC-TT or a control MenC conjugate vaccine, co-administered with diphtheria-33

tetanus-acellular pertussis (DTPa)-based combination vaccines (DTPa/Hib for control 34

groups) and a pneumococcal conjugate vaccine (10-valent pneumococcal non-typeable H. 35

influenzae protein D conjugate vaccine [PHiD-CV] or 7-valent CRM197 conjugate vaccine 36

[7vCRM]). MenC antibody titres were measured by serum bactericidal antibody assay using 37

rabbit complement (rSBA) and antibodies against Hib polyribosylribitol phosphate (anti-38

PRP) by ELISA. Antibody persistence up to 5 years after booster vaccination is reported for 39

530 children aged ~6 years. 40

Results: The percentages of children with seroprotective rSBA-MenC titres were between 41

24.2% and 40.1% in all groups approximately 5 years after booster vaccination. More than 42

98.5% of children in each group retained seroprotective anti-PRP concentrations. No vaccine-43

related serious adverse events and no events related to lack of vaccine efficacy were reported. 44

Conclusion: Approximately 5 years after booster vaccination, the majority of children 45

retained seroprotective anti-PRP antibody concentrations. The percentage of children 46

retaining seroprotective rSBA-MenC titres was low (≤40%), suggesting that a significant 47

proportion of children may be unprotected against MenC disease. 48

49


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Introduction 50

Immunization of children with conjugate vaccines has proven to be a successful strategy to 51

prevent infections caused by various encapsulated bacteria such as Neisseria meningitidis and 52

Haemophilus influenzae type b (Hib) (1), and has resulted in a great decline in the incidence 53

of meningococcal serogroup C (MenC) and Hib disease in the world (2, 3). In addition to 54

immune memory, persisting antibodies have been suggested to be a more appropriate 55

correlate of long-term protection against disease (4). Circulating antibodies are particularly 56

important for sustained protection against invasive MenC disease (5). 57

In Europe, MenC is the second most important cause of invasive meningococcal disease 58

(IMD) after meningococcal serogroup B. In 2012, according to the European Centre for 59

Disease Prevention and Control, 17% of IMD in Europe was caused by MenC (6). In 60

addition, recent estimates from Spain (covering the 2005–2011 period), Germany (2002–61

2010) and Poland (2002–2011) have found that MenC was responsible for 13.2%, 25.0% and 62

36.6% of confirmed IMD cases, respectively (7-9). 63

The Hib and MenC tetanus toxoid (TT) conjugate vaccine (Hib-MenC-TT, Menitorix™; 64

GSK Vaccines) is a combination vaccine containing polyribosylribitol phosphate (PRP) from 65

Hib and polysaccharide from MenC, each individually conjugated to TT as carrier protein. 66

The vaccine was developed to provide protection to infants and toddlers against Hib and 67

MenC diseases in a single injection (10). Hib-MenC-TT offers an alternative vaccination 68

schedule to diphtheria-tetanus-acellular pertussis (DTPa)/Hib combined vaccines co-69

administered with MenC conjugate vaccines. 70

Hib-MenC-TT primary and booster vaccinations with different vaccination schedules and 71

different combination vaccines were shown to be safe and immunogenic in infants and 72

toddlers (11-27). Primary vaccination induced persistent antibodies against both antigens up 73

to the second year of life (12-15). Persistence rates post-booster vaccination varied in 74


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different studies (22, 23, 27), and there are no data available for antibody persistence after co-75

administration with a pneumococcal conjugate vaccine. 76

As mass vaccination schedules expand, there is a risk that adding further antigens to the 77

schedule could lead to unexpected immune interferences (28, 29). If initial immune responses 78

are not as robust as initially expected, the antibody responses may not persist as long as 79

protection is needed. The purpose of this extension study was to explore whether differences 80

in initial antibody concentrations and titres to the co-administered antigens in the Hib-MenC 81

and pneumococcal conjugate vaccines translated into differences in long-term persistence. 82

In the original randomized study, 1548 healthy children were vaccinated with Hib-MenC-TT, 83

or a control MenC conjugate vaccine co-administered with a DTPa or DTPa/Hib-containing 84

vaccine, and a pneumococcal conjugate vaccine. After primary (at 2–4–6 months of age) and 85

booster (at 11–18 months of age) vaccination, immune responses were induced against all 86

vaccine components (16, 17). In the current follow-up study, we evaluated persistence of the 87

immunogenicity of the Hib-MenC-TT conjugate vaccine up to 5 years after booster 88

vaccination, with the evaluation of MenC antibody persistence as primary objective. The 89

antibody persistence to the pneumococcal conjugate vaccines administered in the study will 90

be addressed in a separate publication. 91

92

Materials and Methods 93

Ethical statement 94

The antibody persistence study (ClinicalTrials.gov identifier: NCT00891176) was conducted 95

in Germany, Poland, and Spain between May and December 2009 (Year 2), May and 96

November 2010 (Year 3) and April and November 2012 (Year 5). The protocol was approved 97

by the following Ethics Committees: Comité Ético de Investigación Clínica del Hospital 98

Universitario de Móstoles, Madrid; Comité Ético de Investigación Clínica del Hospital 99


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Clínico San Carlos, Madrid; Komisja Bioetyczna przy Okregowej Izbie Lekarskiej, Krakow; 100

Ethik-Kommission der Bayerischen Landesarztekammer, Munchen; Ethik-Kommission der 101

Landesarztekammer Baden-Wurttemberg, Stuttgart; and Landesamt für Gesundheit und 102

Soziales Geschaftss der Ethik-Kommission des Landes Berlin. The study was conducted in 103

accordance with the principles of Good Clinical Practice and the Declaration of Helsinki, 104

although some deviations in terms of study documentation and adherence to the study 105

protocol were identified. Some additional Good Clinical Practice deviations were noted at 106

one of the study centres, which included the finding that annual reports and updates of 107

protocol amendments and administrative changes had not been sent to regulatory authorities, 108

as required by local law. However, after full investigation by an independent department and 109

discussion with local regulatory agencies, it was determined that these findings did not have 110

an impact on the safety of participants or on data integrity. 111

Study design and participants 112

Written informed consent was obtained from each child’s parent or guardian. Healthy 113

children who completed primary and booster vaccinations in a previous study 114

(ClinicalTrials.gov identifier: NCT00334334/00463437 (17)) and were in the blood sampling 115

subset in the booster study, and whose parents or legal guardians were believed by the 116

investigator to be able to comply with study requirements, were included in this open, long-117

term persistence study. Children were excluded from the persistence study if they had 118

received a MenC, Hib, hepatitis B, or pneumococcal vaccine or had developed MenC, Hib, 119

hepatitis B, or invasive pneumococcal disease since booster vaccination, or had received an 120

immune-modifying drug in the previous 6 months, a blood product in the previous 3 months, 121

or an investigational drug or vaccine in the last 30 days before blood sampling. In the 122

previous primary/booster vaccination study, exclusion criteria included vaccination against 123

diphtheria, tetanus, pertussis, polio, MenC, Hib, hepatitis B, or Streptococcus pneumoniae. 124


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Immunization with vaccines (such as hepatitis B vaccine) where the first dose was given 125

within the first two weeks of life was permitted, in accordance with national 126

recommendations. 127

In the initial phase III, open, randomised, multicentre study (17), Hib-MenC-TT or a control 128

MenC conjugate vaccine (MenC-CRM197 [Meningitec™; Pfizer Inc.] or MenC-TT [NeisVac-129

C™; Baxter Healthcare SA]) were co-administered with a DTPa or DTPa/Hib-containing 130

vaccine (all manufactured by GSK Vaccines) and one of two pneumococcal conjugate 131

vaccines: 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate 132

vaccine (PHiD-CV, Synflorix™; GSK Vaccines) or 7-valent pneumococcal CRM197 133

conjugate vaccine (7vCRM, Prevenar™/Prevnar™; Pfizer Inc.). Hib-MenC-TT, 134

pneumococcal conjugate vaccines, and DTPa-containing vaccines were administered at 2–4–135

6 months of age, with booster vaccination at 11–18 months of age (17). The MenC-TT and 136

MenC-CRM197 vaccines were administered at 2 and 4 months of age (in Poland, to comply 137

with national recommendations, a third dose was offered at approximately 7 months of age) 138

and at 11–18 months of age. 139

There were four study groups: children were randomised (1:1:1:1) to receive Hib-MenC-TT 140

plus either PHiD-CV (Hib-MenC + PHiD-CV group) or 7vCRM (Hib-MenC + 7vCRM 141

group), MenC-CRM197 plus PHiD-CV (MenC-CRM group), or MenC-TT plus PHiD-CV 142

(MenC-TT group) (Table 1). In Germany and Poland, groups administered Hib-MenC-TT 143

were given DTPa-hepatitis B-inactivated polio vaccine (DTPa-HBV-IPV, Infanrix 144

penta™/Pediarix™; GSK Vaccines) and groups administered MenC conjugate vaccines were 145

given DTPa-HBV-IPV/Hib (Infanrix hexa™; GSK Vaccines) as booster vaccination. 146

Because hepatitis B booster vaccination is not recommended in Spain, the Spanish Hib-147

MenC-TT groups received DTPa-IPV (Infanrix-IPV™; GSK Vaccines) while the control 148

groups received DTPa-IPV/Hib (Infanrix-IPV/Hib™; GSK Vaccines) as booster vaccination. 149


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In Poland, children received a single dose of hepatitis B vaccine at birth, according to 150

national recommendations. 151

Study objectives 152

The primary objective of this follow-up study was to evaluate the MenC antibody persistence 153

after vaccination in all treatment groups that received the Hib-MenC-TT conjugate vaccine, 154

in terms of percentage of children with serum antibody levels above the assay cut-off up to 60 155

months after booster vaccination (72–76 months of age). In this report, antibody persistence 156

results are presented for blood samples taken from children at approximately 3, 4 and 6 years 157

of age. The secondary objectives included the evaluation of antibody persistence with respect 158

to Hib capsular polysaccharide (anti-PRP) and hepatitis B surface antigen (anti-HBs) 159

antibody concentrations. 160

Immunogenicity assessments 161

Blood samples of approximately 5 mL were collected at 36–40 months of age (i.e. 162

approximately 24 months after booster vaccination), 48–52 months of age (i.e. approximately 163

36 months after booster vaccination) and at 72–76 months of age (i.e. approximately 60 164

months after booster vaccination). 165

Antibodies against MenC at Year 5 were measured by serum bactericidal activity assay 166

performed at Public Health England (PHE), using rabbit complement (rSBA) with a cut-off 167

of 1:8 as indication of protection (30). Earlier time points were tested with an in-house rSBA-168

MenC assay performed at GSK Vaccines (16), which prevents a direct comparison of the 169

Year 5 results with the initial results from earlier study time points (17). 170

Anti-PRP antibodies were assessed by an in-house ELISA performed at GSK Vaccines, for 171

which concentration levels ≥0.15 µg/mL and ≥1 µg/mL are considered indicative of short- 172

and long-term protection, respectively (31, 32). 173

Antibodies against hepatitis B were assessed at GSK Vaccines’ laboratories using the 174


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commercial chemiluminescence immunoassay Centaur™ (Siemens Healthcare Diagnostics). 175

Anti-HBs seroprotection was defined as an antibody concentration above 10 milli-176

international units (mIU)/mL (33). 177

Safety assessments 178

Serious adverse events (SAEs) for the primary and booster phases of this study were reported 179

earlier (34). In this study, SAEs which were assessed by the investigator as potentially 180

vaccine- or study procedure-related or due to lack of vaccine efficacy were documented 181

retrospectively following booster vaccination and recorded at every visit/contact during the 182

study. Per definition, an SAE was any untoward medical occurrence that resulted in death, 183

was life-threatening, required hospitalization or resulted in disability/incapacity. Although it 184

was unlikely for SAEs related to vaccination to occur so late after vaccination, this study was 185

designed to ensure that any event that was only manifested long after vaccination and which 186

the investigator thought could have been related to the vaccination or any event related to 187

lack of vaccine efficacy during this long-term persistence phase and that fulfil the definition 188

of an SAE would be recorded. 189

Statistical analyses 190

Results are presented for the according-to-protocol (ATP) cohorts for antibody persistence 191

post-booster vaccination, which included all eligible children who received the full primary 192

and booster vaccination course corresponding to their group, were compliant with study 193

procedures and who had available assay results. 194

For each group, the percentages of participants retaining antibody concentrations or titres 195

above the predefined thresholds and geometric mean antibody titres and concentrations 196

(GMTs and GMCs) were calculated with associated 95% confidence intervals (CIs). 197

Exploratory statistical analyses were performed in which potential differences between 198

groups were defined when the asymptotic standardised 95% CI for the difference in 199


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percentages of children with titres or concentrations above proposed cut-offs between the two 200

groups did not contain the value “0”, or when the 95% CI for the GMT/GMC ratios between 201

groups did not contain the value “1”. This analysis was performed using a one-way analysis 202

of variance model on the logarithm in base 10 (log10) transformation of the titres or 203

concentrations using the vaccine group and country as the only covariates. 204

The results of all exploratory group comparisons should be interpreted with caution 205

considering that there was no adjustment for multiplicity for these comparisons and the 206

clinical relevance of the differences was not pre-specified. 207

The statistical analyses were performed using the Statistical Analysis Systems (SAS®

; Cary, 208

NC, USA) version 9.22 on Windows. 209

210

Results 211

Study participants 212

Of the 1437 children who were part of the total enrolled cohort for the booster phase, 581, 213

561 and 539 were included in the total enrolled cohorts for persistence at 24, 36 and 60 214

months post-booster vaccination, respectively. The ATP cohorts for antibody persistence 215

included 571 children at 24 months post-booster vaccination, 543 children at 36 months post-216

booster vaccination and 530 children at 60 months post-booster vaccination. Reasons for 217

exclusion from the ATP cohorts and the distribution per study group are given in Figure 1. 218

Across the four vaccine groups, the mean age of the children in the ATP cohorts for 219

persistence was similar between groups, and the majority was of European descent (Table 2). 220

The proportions of males and females were similar across all groups, with a higher proportion 221

of males in the MenC-TT group and a higher proportion of females in the Hib-MenC + 222

PHiD-CV group. The gender and racial distribution in the ATP cohorts for persistence were 223

consistent with the primary study (17). 224


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Immunogenicity against MenC 225

Approximately 5 years post-booster vaccination, the percentage of children with an rSBA-226

MenC titre ≥8 as measured by the PHE assay was between 24.2% and 40.1% in all groups, 227

with the highest value observed in the MenC-TT group (Table 3). GMTs ranged from 7.2 in 228

the MenC-CRM group to 11.9 in the MenC-TT group. At Year 3, rSBA-MenC titres ≥8 as 229

measured by the GSK assay were retained by at least 72.4% of children in each group 230

(Supplementary Table 1). 231

Based on exploratory analyses, the percentage of children with rSBA-MenC titre ≥8 at Year 5 232

was higher in the MenC-TT and Hib-MenC + PHiD-CV groups compared to MenC-CRM 233

group, and in the MenC-TT group compared to the Hib-MenC + 7vCRM group (Table 4). 234

The rSBA-MenC GMT was higher in the MenC-TT group compared to MenC-CRM group. 235

No difference between MenC-TT and Hib-MenC + PHiD-CV groups was observed. Similar 236

observations were made at Year 3 (Supplementary Table 2). 237

Immunogenicity against Hib PRP 238

Approximately 5 years post-booster vaccination, the percentage of children with anti‐PRP 239

concentrations ≥0.15 μg/mL remained high in all groups (≥98.5%) (Table 5). Among all 240

groups, at least 57.5% of children had anti‐PRP concentrations ≥1 μg/mL, with the highest 241

percentages in the Hib-MenC-TT recipients (Hib-MenC + PHiD-CV and Hib-MenC + 242

7vCRM groups). Anti-PRP GMCs at Year 5 ranged from 1.65 in the MenC-TT group to 2.95 243

in the Hib-MenC + PHiD-CV group. 244

Based on exploratory analyses, there was no significant potential difference between groups 245

in percentages of children achieving anti-PRP antibody concentrations ≥0.15 µg/mL. Anti-246

PRP antibody GMCs were lower in the control MenC vaccines recipients than in the Hib-247

MenC-TT groups, regardless of MenC vaccine type, and there was no difference in anti-PRP 248

antibody GMCs between the two MenC vaccine groups (Table 6). 249


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Immunogenicity against hepatitis B 250

Considering the anti-HBs results as tested by chemiluminescence assay, at least 72.8% of 251

children had antibody concentrations ≥10 mIU/mL approximately 60 months post-booster 252

vaccination (Table 7). Anti-HBs antibody GMCs declined by 60 months post-booster 253

vaccination and were between 45.7 and 85.4 mIU/mL at 60 months post-booster vaccination. 254

Safety 255

No SAEs considered by the investigator to be potentially vaccine- or study procedure-related 256

or due to lack of vaccine efficacy were reported following administration of the booster 257

vaccination. 258

259

Discussion 260

This study reports the antibody persistence in healthy children up to 5 years after the Hib and 261

MenC full vaccination course. At the time the study was conducted, children in the United 262

Kingdom (UK) used to receive concomitant doses with Hib-MenC and pneumococcal 263

conjugate vaccines as primary vaccinations. Our data are important in comparing persistence 264

post-booster vaccination, since children in the UK currently receive booster doses of Hib-265

MenC and pneumococcal conjugate vaccines simultaneously at 12–13 months of age (35). 266

For MenC, the percentages of children retaining seroprotective rSBA-MenC titres at Year 5 267

post-booster vaccination were 24.2%, 25.4%, 38.5% and 40.1% in the MenC-CRM, Hib-268

MenC + 7vCRM, Hib-MenC + PHiD-CV and MenC-TT groups, respectively. In contrast, 269

retention of anti-PRP antibodies was nearly universal in all groups: at least 98.5% of children 270

in each group were observed to have anti-PRP concentrations ≥0.15 μg/ml, 5 years post-271

booster vaccination. 272

The percentages of children with seroprotective rSBA-MenC titres ≥8 were considerably 273

lower than the 72.4%–96.4% rates reported three years after booster vaccination. However, 274


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the assays were performed in different laboratories with different procedures, and therefore 275

the results cannot be directly compared. It has been observed that the GSK rSBA-MenC 276

assay used previously has a higher sensitivity than the PHE rSBA-MenC assay used in the 277

current follow-up study, especially to naturally acquired antibodies (36). In addition, the PHE 278

laboratory uses the discontinuous method to interpolate titres from the standard curve as 279

opposed to GSK, which uses a continuous method. The discontinuous method of titre 280

calculation is known to result in lower titres than the continuous method. 281

The proportions of children with seroprotective rSBA-MenC titres ≥8 in our study were 282

consistent with the 22%–43% rates reported in a previous study in the UK (measured with the 283

same rSBA assay at PHE) at 24 months after the administration of a Hib-MenC-TT booster 284

dose in toddlers (12–14 months of age) (19). In this study, infants had been primed with two 285

doses of MenC-CRM or MenC-TT at 2 and 3, or 2 and 4 months of age (19). In contrast, in a 286

study in Spain, where the GSK Vaccines rSBA-MenC assay was used, higher percentages 287

were observed more than 5 years after Hib-MenC-TT booster vaccination in toddlers 288

following Hib-MenC-TT or MenC-TT priming in infancy in a 2-4-6-month schedule (78%–289

97%) (23). However, these results cannot be directly compared with the current study results 290

as different rSBA assay procedures were used. 291

The low MenC titres at 5 years post-vaccination suggested that individuals may no longer be 292

protected or contribute to herd immunity. The introduction of a MenC adolescent booster 293

dose at around 14 years has been adopted in the UK in 2013 based on advice from the Joint 294

Committee on Vaccination and Immunisation (37). The adolescent booster vaccination at 12 295

years of age was also incorporated in the vaccination calendar of all Spanish autonomous 296

regions in 2014 (7). 297

The exploratory analyses revealed possible differences between groups in MenC antibody 298

persistence. The percentage of children with an rSBA-MenC titre ≥8 at Year 5 post-booster 299


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vaccination was higher in the MenC-TT and Hib-MenC + PHiD-CV groups compared to 300

MenC-CRM group, and in the MenC-TT group compared to the Hib-MenC + 7vCRM group. 301

MenC GMTs were observed to be higher in the MenC-TT group versus the MenC-CRM 302

group, which is consistent with previous observations suggesting that TT was a better carrier 303

protein for MenC priming than CRM197 in terms of seroprotection and GMTs (19, 38). 304

A clear effect of the co-administered pneumococcal conjugate vaccines could not be 305

observed, since there were no significant potential differences in terms of MenC GMTs 306

between PHiD-CV and 7vCRM recipients. Moreover, the control vaccines MenC-CRM and 307

MenC-TT were only co-administered with PHiD-CV; no groups receiving these control 308

MenC vaccines together with 7vCRM were included in this study. 309

High seroprotection rates against the Hib antigen were observed in all groups. There was no 310

significant potential difference between groups in the percentage of children with anti-PRP 311

antibody concentration ≥0.15 μg/mL, and no decline compared to earlier time points. 312

Comparison of anti-PRP antibody GMCs between groups showed better long-term 313

persistence 5 years post-booster vaccination in the Hib-MenC-TT recipients compared to the 314

DTPa/Hib recipients, regardless of the co-administered pneumococcal conjugate vaccine, 315

which is consistent with a previous report (23). There was only a slight decrease in the Year 5 316

anti-PRP antibody GMC values compared to the previous time points (up to 3 years post-317

booster vaccination). The high anti-PRP antibody persistence in all groups suggests that an 318

additional Hib booster dose is not needed. 319

Infants and toddlers are routinely vaccinated against hepatitis B in many countries with the 320

expectation that such vaccination will protect against infections that may be acquired years in 321

the future. The purpose of assessing the hepatitis B antibody persistence was to explore the 322

percentage of subjects retaining seroprotective antibody concentrations 5 years after 323

vaccination with the various regimens. Our results showed that the anti-HBs seroprotection 324


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rates 5 years post-booster vaccination ranged from 73% to 84% in all groups. These 325

percentages appeared to be smaller compared to earlier time points (2 and 3 years post-326

booster vaccination). However, statistical comparisons were not performed and therefore, the 327

anti-HBs data from our study must be interpreted with caution. 328

In conclusion, 5 years post-booster vaccination, protective anti-PRP antibody concentrations 329

persisted in at least 98.5% of children in all groups, but the protective rSBA-MenC antibody 330

titres were shown to persist only in 24.2–40.1% of the children, with the highest values in the 331

Hib-MenC + PHiD-CV and MenC-TT groups. These results are consistent with previously 332

reported Hib-MenC-TT vaccine data. No SAEs considered possibly related to vaccination 333

were reported during the 5-year persistence phase of the study. 334

335

Funding information 336

GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of 337

the clinical trial conduct and analysis. GlaxoSmithKline Biologicals SA also took in charge 338

all costs associated with the development and the publishing of the present manuscript. All 339

authors had full access to the data. MVW and DK are employees of the GSK group of 340

companies. YB was an employee of the GSK group of companies and is co-inventor of a 341

patent which, if granted, will be owned by the GSK group of companies. YB and MVW own 342

stock options and stock grants in the GSK group of companies. JCT, JB, RK and DG have no 343

conflict of interest. 344

345

Acknowledgements 346

The authors thank the children and their families for participating in this trial, and all 347

investigators and their clinical teams for their contribution to this study. The authors also 348

thank Melissa McNeely (XPE Pharma & Science c/o GSK Vaccines) for publication 349


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management and Vasile Coman (XPE Pharma & Science) for drafting the manuscript. 350

351

Authors’ contributions 352

JCT, JB, RK, DG, DK and MVW conceived and designed the experiments. JCT, JB, RK and 353

DG performed the experiments. DK and MVW analyzed the data. JCT, JB, RK, DG, DK, YB 354

and MVW contributed with reagents, materials and/or analysis tools. JCT, YB, JB, RK, DG, 355

DK and MVW wrote the paper. 356

357

Trademarks 358

Menitorix, Priorix, Hiberix, Infanrix-IPV and Infanrix-IPV/Hib are trademarks of the GSK 359

group of companies. Meningitec is a trademark of Nuron Biotech. NeisVac-C is a trademark 360

of Pfizer. ADVIA Centaur is a trademark of Siemens Healthcare Diagnostics. 361

362

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months. Pediatr Infect Dis J 29:148-152. 529

530


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Table 1. Study groups 531

Group MenC

vaccine

Pneumococcal

vaccine Co-administered vaccine

Hib-MenC + PHiD-CV Hib-MenC-TT PHiD-CV DTPa-HBV-IPV or DTPa-IPVb

Hib-MenC + 7vCRM Hib-MenC-TT 7vCRM DTPa-HBV-IPV or DTPa-IPVb

MenC-CRMa MenC-CRM PHiD-CV DTPa-HBV-IPV/Hib or DTPa-IPV/Hibb

MenC-TTa MenC-TT PHiD-CV DTPa-HBV-IPV/Hib or DTPa-IPV/Hibb

Primary vaccination phase: doses at 2, 4, and 6 months. Booster phase: vaccines administered at 11–18 months. 532

aMenC-CRM and MenC-TT vaccines were administered at 2 and 4 months of age; in Poland, to comply with 533

national recommendations, children were offered a third dose of MenC vaccines at ±7 months of age. 534

bBecause hepatitis B booster vaccination is not recommended in Spain, the Spanish Hib-MenC-TT groups 535

received DTPa-IPV while the control groups received DTPa-IPV/Hib as booster vaccination. 536


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Table 2. Demographic characteristics of the study children (ATP cohorts for antibody persistence at 24 (Y2), 36 (Y3) and 60 months (Y5) post-537

booster vaccination) 538

Timepoint N

Hib-MenC

+ PHiD-CV

N

Hib-MenC

+ 7vCRM

N MenC-CRM N MenC-TT

Mean age SD (months)

Y2 144 37.3 1.2 140 37.3 1.3 141 37.1 1.2 146 37.2 1.2

Y3 133 49.2 1.5 136 48.7 1.2 136 48.8 1.3 138 48.7 1.1

Y5 131 72.9 1.0 134 72.9 1.2 128 72.8 1.0 137 72.9 1.1

Gender (%)

Female

Y2 144 57.6 140 50.7 141 50.4 146 44.5

Y3 133 60.2 136 52.2 136 50.7 138 43.5

Y5 131 58.8 134 50.7 128 49.2 137 46.0

Ethnicity (%)

European descent

Y2 144 95.1 140 100 141 95.7 146 98.6

Y3 133 95.5 136 99.3 136 96.3 138 97.8

Y5 131 96.2 134 99.3 128 96.9 137 97.8

N, total number of children per group. 539


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Table 3. Serum bactericidal activity against MenC approximately 5 years post-booster 540

vaccination (ATP cohort for antibody persistence at 60 months post-booster vaccination) 541

rSBA-MenC (95% CI)

Group N % ≥8 GMT

Hib-MenC + PHiD-CV 130 38.5 (30.1 – 47.4) 10.1 (7.9 – 12.9)

Hib-MenC + 7vCRM 134 25.4 (18.3 – 33.6) 8.5 (6.6 – 11.1)

MenC-CRM 128 24.2 (17.1 – 32.6) 7.2 (5.8 – 8.9)

MenC-TT 137 40.1 (31.9 – 48.9) 11.9 (8.9 – 16.0)

N, total number of children with available results. 542

543


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Table 4. Differences between groups (first group minus second group) in percentages of 544

children with rSBA-MenC titres above the threshold and rSBA-MenC GMT ratios (first 545

group over second group) approximately 5 years post-booster vaccination (exploratory 546

analyses; ATP cohort for antibody persistence at 60 months post-booster vaccination) 547

rSBA-MenC (95% CI)a

Group comparison Difference in % of children

achieving ≥8

GMT ratio

MenC-CRM

vs. MenC-TT -15.93 (-26.79; -4.67) 0.68 (0.47; 0.96)

MenC-CRM

vs. Hib-MenC + PHiD-CV -14.24 (-25.26; -2.92) 0.73 (0.53; 1.01)

MenC-CRM

vs. Hib-MenC + 7vCRM -1.15 (-11.62; 9.39) 0.92 (0.67; 1.28)

MenC-TT

vs. Hib-MenC + PHiD-CV 1.68 (-10.02; 13.32) 1.15 (0.79; 1.68)

MenC-TT

vs. Hib-MenC + 7vCRM 14.77 (3.59; 25.62) 1.38 (0.95; 2.01)

a95% CIs of differences not including 0 were regarded as indicative that a significant potential difference might exist 548

between groups. For GMT ratio, 95% CIs not including 1 indicated that a significant potential difference might exist. BOLD 549

= comparison for which the exploratory analysis suggests that a potentially significant difference may exist. 550

551


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Table 5. Anti-PRP antibody persistence (ATP cohort for antibody persistence at 60 months 552

post-booster vaccination) 553

Anti-PRP antibodies (95% CI)

Group Time point N % ≥0.15 µg/mL % ≥1 µg/mL GMC

Hib-MenC

+ PHiD-CV

Post-primary 130 98.5 (94.6; 99.8) 97.7 (93.4; 99.5) 13.71 (11.11; 16.93)

Post-booster: M1 130 100 (97.2; 100) 100 (97.2; 100) 90.53 (75.73; 108.23)

Post-booster: M24 121 100 (97.0; 100) 93.4 (87.4; 97.1) 4.21 (3.41; 5.21)

Post-booster: M36 122 100 (97.0; 100) 90.2 (83.4; 94.8) 3.76 (3.03; 4.66)

Post-booster: M60 130 100 (97.2; 100) 84.6 (77.2; 90.3) 2.95 (2.40; 3.62)

Hib-MenC

+ 7vCRM

Post-primary 132 100 (97.2; 100) 97.0 (92.4; 99.2) 10.70 (8.87; 12.90)

Post-booster: M1 130 100 (97.2; 100) 100 (97.2; 100) 65.65 (52.76; 81.69)

Post-booster: M24 125 100 (97.1; 100) 84.8 (77.3; 90.6) 3.77 (3.04; 4.69)

Post-booster: M36 125 99.2 (95.6; 100) 79.2 (71.0; 85.9) 2.80 (2.27; 3.46)

Post-booster: M60 132 100 (97.2; 100) 75.8 (67.5; 82.8) 2.56 (2.07; 3.17)

MenC-CRM Post-primary 127 98.4 (94.4; 99.8) 86.6 (79.4; 92.0) 4.23 (3.36; 5.32)

Post-booster: M1 127 100 (97.1; 100) 99.2 (95.7; 100) 33.49 (27.11; 41.37)

Post-booster: M24 118 100 (96.9; 100) 78.0 (69.4; 85.1) 2.51 (1.99; 3.16)

Post-booster: M36 123 99.2 (95.6; 100) 67.5 (58.4; 75.6) 1.94 (1.56; 2.41)

Post-booster: M60 127 99.2 (95.7; 100) 66.9 (58.0; 75.0) 1.66 (1.34; 2.05)

MenC-TT Post-primary 135 100 (97.3; 100) 95.6 (90.6; 98.4) 6.48 (5.48; 7.67)

Post-booster: M1 134 100 (97.3; 100) 100 (97.3; 100) 36.35 (30.22; 43.73)

Post-booster: M24 130 100 (97.2; 100) 77.7 (69.6; 84.5) 2.29 (1.84; 2.85)

Post-booster: M36 128 99.2 (95.7; 100) 62.5 (53.5; 70.9) 1.78 (1.42; 2.24)

Post-booster: M60 134 98.5 (94.7; 99.8) 57.5 (48.6; 66.0) 1.65 (1.30; 2.09)

N, total number of children with available results; Post-primary, 1 month after third dose at 6 months of age; 554

Post-booster: M1, 1 month after booster vaccination; Post-booster: M24, approximately 24 months after booster 555

vaccination; Post-booster: M36, approximately 36 months after booster vaccination; Post-booster: M60, 556

approximately 60 months after booster vaccination. 557

558


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Table 6. Differences between groups (first group minus second group) in percentages of 559

children with anti-PRP antibody concentrations above the threshold and anti-PRP GMC 560

ratios (first group over second group) approximately 5 years post-booster vaccination 561

(exploratory analyses; according-to-protocol cohort for antibody persistence at 60 months 562

post-booster vaccination) 563

Anti-PRP antibodies (95% CI)a

Group comparison Difference in % of children

achieving ≥0.15 µg/mL

Difference in % of children

achieving ≥1 µg/mL GMC ratio

MenC-CRM

vs. MenC-TT 0.71 (-2.97; 4.59) 9.47 (-2.34; 20.99) 0.96 (0.70; 1.31)

MenC-CRM

vs. Hib-MenC + PHiD-CV -0.79 (-4.34; 2.11) -17.69 (-27.93; -7.31) 0.54 (0.41; 0.73)

MenC-CRM

vs. Hib-MenC + 7vCRM -0.79 (-4.34; 2.06) -8.83 (-19.76; 2.20) 0.64 (0.47; 0.87)

MenC-TT

vs. Hib-MenC + PHiD-CV -1.49 (-5.29; 1.41) -27.15 (-37.34; -16.49) 0.56 (0.41; 0.75)

MenC-TT

vs. Hib-MenC + 7vCRM -1.49 (-5.29; 1.37) -18.29 (-29.18; -6.99) 0.65 (0.47; 0.89)

a95% CIs of differences not including 0 were regarded as indicative that a significant potential difference might 564

exist between groups. For GMC ratio, 95% CIs not including 1 indicated that a significant potential difference 565

might exist. BOLD = comparison for which the exploratory analysis suggests that a potentially significant 566

difference may exist. 567

568


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Table 7. Anti-HBs antibody persistence at Year 5 post-booster vaccination, as assessed by a 569

chemiluminescence assay (ATP cohort for antibody persistence at 60 months post-booster 570

vaccination)a

571

Anti-HBs antibodies (95% CI)

Group Time point N % ≥10 mIU/ml GMC, mIU/mL

Hib-MenC +

PHiD-CV

Post-booster: M24 122 88.5 (81.5; 93.6) 154.5 (106.8; 223.5)

Post-booster: M36 118 84.7 (77.0; 90.7) 92.3 (63.8; 133.6)

Post-booster: M60 125 72.8 (64.1; 80.4) 45.7 (32.2; 64.8)

Hib-MenC +

7vCRM

Post-booster: M24 119 93.3 (87.2; 97.1) 218.9 (152.4; 314.4)

Post-booster: M36 119 89.9 (83.0; 94.7) 142.5 (100.3; 202.6)

Post-booster: M60 128 84.4 (76.9; 90.2) 85.4 (60.4; 120.6)

MenC-CRM

Post-booster: M24 118 92.4 (86.0; 96.5) 211.1 (147.1; 303.1)

Post-booster: M36 120 86.7 (79.3; 92.2) 130.8 (91.9; 186.2)

Post-booster: M60 122 82.0 (74.0; 88.3) 66.7 (47.2; 94.1)

MenC-TT

Post-booster: M24 130 90.8 (84.4; 95.1) 189.2 (134.2; 266.7)

Post-booster: M36 127 88.2 (81.3; 93.2) 128.4 (91.3; 180.6)

Post-booster: M60 129 79.8 (71.9; 86.4) 64.7 (46.4; 90.2)

N, total number of children with available results; Post-booster: M24, approximately 24 months after booster 572

vaccination; Post-booster: M36, approximately 36 months after booster vaccination; Post-booster: M60, 573

approximately 60 months after booster vaccination. 574

aNote that a booster vaccination of HBV was not given in Spain, in accordance with national recommendations. 575

Data shown here includes subjects from all countries combined. 576

577


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Figure Legend 578

579

Figure 1. Disposition of study children and reasons for exclusion from ATP cohorts for 580

persistence at 24, 36 and 60 months post-booster vaccination. 581

582


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Figure 1. 583

584

N, number of study participants for specified group 585


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Downloaded from on May 23, 2020 by guest · 4/28/2016 · 36 influenzae protein D conjugate vaccine [ PHiD -CV] or 7 -valent CRM 197 conjugate vaccine 37 [7vCRM ]). MenC antibody