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Immunogenicity, Safety, and Antibody Persistence at 3, 5 and 10 Years Postvaccination in 1

11-14 Year-Old Adolescents Randomized to Booster Immunization with a Combined 2

Tetanus, Diphtheria, 5-Component Acellular Pertussis, and Inactivated Poliomyelitis 3

Vaccine (Tdap-IPV; Adacel-Polio®) Administered with a Hepatitis B Vaccine (HepB; 4

RECOMBIVAX HB®) Concurrently or 1 Month Apart 5

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Running Title: Adacel-Polio plus HepB booster in adolescents 7

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Joanne Embreea, Barbara Law

a1, Tim Voloshen

b, Antigona Tomovici

c# 9

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aUniversity of Manitoba, Winnipeg, MB, Canada 11

bSanofi Pasteur, Swiftwater, PA, USA 12

cSanofi Pasteur, Toronto, ONT, Canada 13

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Corresponding Author: Antigona Tomovici, Sanofi Pasteur, 1755 Steeles Avenue West, 15

Toronto, ONT, M2R 3T4, Canada; TEL: +1 416 667 2273; FAX: +1 416 667 2231; E-mail: 16

(miggi.tomovici@sanofipasteur .com) 17

1 Current affiliation: Public Health Agency of Canada, Ottawa, Canada

CVI Accepts, published online ahead of print on 24 December 2014Clin. Vaccine Immunol. doi:10.1128/CVI.00682-14Copyright © 2014, American Society for Microbiology. All Rights Reserved.

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Abstract 18

An understanding of antibody persistence elicited by combined tetanus, diphtheria, 5-component 19

acellular pertussis and inactivated poliovirus vaccine (Tdap-IPV) after adolescent vaccination is 20

important to optimize booster dosing intervals. Our objectives were to compare safety and 21

immunogenicity in adolescents of Tdap-IPV coadministered with HepB to sequential 22

administration and evaluate humoral immunity 3, 5, and 10 years after Tdap-IPV vaccination. 23

This phase II randomized, controlled, open-label study enrolled 280 11- to 14-year-old 24

adolescents with up to 10 years postvaccination follow-up. Group 1 (n=145) received Tdap-IPV 25

followed by a HepB dose one month later; Group 2 (n=135) received both vaccines 26

simultaneously. No consistent increases in solicited reactions or unsolicited adverse events 27

occurred with coadministration. All vaccinees attained seroprotective antibody levels at ≥0.01 28

IU/mL for diphtheria and tetanus; ≥1:8 dilution for poliovirus (serotypes 1, 2, 3); and ≥10 29

mIU/mL for hepatitis B at 1 month postvaccination. Clinically relevant immunologic interactions 30

did not occur with coadministration. For pertussis, all participants achieved seropositivity levels 31

(≥lower limit of quantitation) and 72.7%–95.8% had 4-fold increases in pertussis antibodies 1 32

month post-vaccination. At 10 years postvaccination, remaining participants (62.8% of the 33

original cohort) maintained seroprotective levels of ≥0.01 IU/mL for diphtheria and tetanus, ≥1:8 34

for all 3 poliovirus serotypes, and 74.1%–98.2% maintained pertussis seropositivity levels 35

depending on the antigen tested. There were no differences between groups. These results 36

support coadministration of Tdap-IPV and HepB to adolescents and suggest that vaccination 37

with Tdap-IPV can offer protection for 10 years after adolescent booster vaccination. 38

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Keywords: combination vaccines; adolescent booster; safety; immunogenicity; antibody 40

persistence; long-term follow-up 41

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INTRODUCTION 43

Despite widespread childhood immunization with pertussis vaccines, recurrence of pertussis has 44

been reported among adolescents and young adults with periodic outbreaks in several countries, 45

suggesting early waning of immunity (1-8). In these outbreaks, high rates of pertussis infection 46

were observed among infants aged <1 year, and the incidence in adolescents aged 10–14 years 47

was also increased. 48

In addition to pertussis morbidity in infected adolescents and adults, these patients 49

constitute a major source of transmission to infants, especially those <6 months of age who are at 50

highest risk of serious disease and death (3, 9). Thus, pertussis immunization of adults and 51

adolescents is recommended for both personal protection and to reduce exposure of vulnerable 52

infants (10, 11). Current recommendations for adolescent vaccination in some European 53

countries and most Canadian provinces include combined tetanus, diphtheria, and acellular 54

pertussis (Tdap) and hepatitis B (HepB) vaccines (12). In Canada, the incidence of reported 55

pertussis decreased in all age groups after the National Advisory Committee on Immunization 56

(NACI) recommended inclusion of a tetanus-diphtheria-acellular pertussis (Tdap) booster to 57

adolescents 14-16 years of age (12). 58

Long-term antibody persistence information after adolescence Tdap vaccination has 59

become available in recent years (13-20). In general, antibody levels are highest 1 month 60

postvaccination and decrease over time (13-15, 17); by 10 years postvaccination, antibody 61

concentrations return to levels comparable or approaching those observed before vaccination 62

(19). 63

One strategy for improved health care for adolescents and young adults is vaccination 64

programs targeted at vaccine-preventable illnesses that they are at high risk of acquiring. 65


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Coadministration of Tdap combination vaccine with HepB vaccine in early adolescence would 66

facilitate more cost-effective adolescent vaccination strategies. It would also help attain 67

immunization target levels by decreasing the number of health care visits needed to complete 68

vaccination schedules. Long-term humoral immunity follow-up assessments may help select 69

optimal dosing intervals for future booster vaccinations after adolescence. The objective of this 70

study was to determine the safety and immunogenicity of Tdap-IPV followed by a dose of HepB 71

vaccine one month later compared with Tdap-IPV and HepB vaccine administered concurrently 72

in adolescents 11–14 years of age and evaluate humoral immunity at 3, 5, and 10 years after 73

Tdap-IPV vaccination. 74

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MATERIALS AND METHODS 76

Study design. This was a phase II, open-label, randomized, controlled study conducted at the 77

University of Manitoba, with vaccinations conducted between January 1999 and May 2000. The 78

study was approved by the University of Manitoba Ethics Committee; signed, witnessed 79

informed consent was obtained from parents or legal guardians of the participants prior to the 80

first study intervention. 81

Randomization was performed by the trial statistician and staff who were not involved in 82

the clinical aspects of the trial. Assignment to Group 1 or Group 2 was performed in a 1:1 ratio 83

via telephone at the time of consent. Group 1 received Tdap-IPV followed by HepB 84

approximately 1 month later. Group 2 received Tdap-IPV and HepB concurrently. The second 85

and third doses of HepB were given 1 month and 6 months after the initial HepB vaccination in 86

both groups. All participants kept daily diaries and were assessed for safety for 2 weeks by the 87

study team. For immunogenicity, participants had blood draws immediately before vaccination, 1 88

month after Tdap-IPV (with or without HepB) vaccination, and 1 month after the last HepB dose 89

for hepatitis B antibody levels. All participants were contacted and asked to return for additional 90

blood draws and subsequent Tdap-IPV serology testing at 3, 5, and 10 years in 2002, 2004, and 91

2009 respectively. Hep B serology was not performed at the subsequent time points. Follow-up 92

was designed as an open-label, long-term assessment of persistence of Tdap-IPV vaccine-elicited 93

antibodies. 94

Participants. At study entry, participants were 11-14 years of age and in good health 95

based on reported medical history. Exclusion criteria included immunodeficiency, 96

immunosuppression or receipt of high-dose steroids; any substantial underlying chronic disease, 97

including malignancy; known impairment of neurologic function or seizure disorder of any 98


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etiology; known or suspected allergy to any vaccine components in the study; receipt of any 99

pertussis, diphtheria, tetanus, or poliomyelitis containing vaccines or HepB vaccine within the 100

previous 5 years; history of physician-diagnosed or laboratory-confirmed pertussis disease within 101

the previous 2 years; receipt of blood products or immunoglobulin within the previous 3 months; 102

receipt of any vaccine within 2 weeks of any study vaccine administration; or daily use of 103

nonsteroidal anti-inflammatory drugs (NSAIDS). To ensure the follow-up populations were 104

representative of the original study participants in terms of immunogenicity, baseline 105

immunogenicity measurements with respect to prevaccination and 1 month postvaccination were 106

assessed for all vaccine antigens for participants at each follow-up period. For the long-term 107

follow-up, participants who were diagnosed with pertussis or received any Td or Tdap vaccine 108

after study vaccine were excluded from analysis. 109

Vaccines. Both vaccines required intramuscular administration with a needle no shorter 110

than 25 mm (1 inch). A single 0.5-mL dose of the Tdap vaccine with inactivated poliomyelitis 111

vaccine (Tdap-IPV; Adacel-Polio®

) contained tetanus (5 Lf) and diphtheria (2 Lf) toxoids 112

adsorbed combined with acellular component pertussis (2.5 µg pertussis toxoid [PT], 5 µg 113

filamentous hemagglutinin [FHA], 3 µg pertactin [PRN], 5 µg fimbriae 2+3 [FIM]) and 114

inactivated poliomyelitis vaccine (poliovirus types 1, 2, 3 at 40 D, 8 D and 32 D antigen units 115

respectively) grown in Vero cells (21). This vaccine also contained 1.3 mg aluminum phosphate, 116

0.6% 2-phenoxyethanol, and polysorbate 80 as excipients. A single dose of the recombinant 117

HepB vaccine (RECOMBIVAX HB®

) contained 5μg hepatitis B virus surface antigen (HBsAg) 118

(22). The vaccines administered in the study were Tdap-IPV manufactured by Sanofi Pasteur 119

Limited (Lot 15001-11) and Hep B vaccine manufactured by Merck & Co. Inc (Lot C004370). 120


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Serological assays. Serological assays were performed by Sanofi Pasteur. The Global 121

Clinical Immunology Laboratory (GCI, USA) performed diphtheria and tetanus assays on the 5-122

year samples and all assays on the 10-years samples. The Clinical Immunology Platform Canada 123

(CIP-CA) performed all baseline, 1-month, and 3-year postvaccination assays and pertussis 124

assays of the 5-year samples. All assays were determined to be concordant between laboratories 125

or adjustment factors were used to make the data concordant. 126

Prevaccination and 1 month postvaccination sera were assayed in parallel; follow-up sera 127

were assayed separately shortly after collection at the 3, 5, and 10-year sampling times. Anti-128

tetanus antibody concentrations were measured by enzyme-linked immunosorbent assay 129

(ELISA) and expressed as International Units (IU)/mL. Diphtheria antibody responses were 130

measured by microneutralization assay and expressed as IU/mL. Antibody titers to poliovirus 131

serotypes 1, 2, and 3 were measured by microneutralization assay and expressed as the inverse 132

serum dilution able to neutralize 50% of the challenge virus. Antibody levels to PT, FHA, PRN, 133

and FIM were measured by ELISA and expressed in ELISA units (EU)/mL. Because there are no 134

universally accepted correlates of pertussis protection, seropositivity was evaluated by 135

determining by the proportion of participants with antibody levels ≥ the lower limit of 136

quantitation (LLOQ) (23). For assays performed at CIP-CA, LLOQs were 5 EU/mL for PT, 3 137

EU/mL for FHA, 3 EU/mL for PRN, and 17 EU/mL for FIM; for the assays performed at GCI, 138

LLOQs were 4 EU/mL for PT, PRN, and FIM and 3 EU/mL for FHA; seropositivity results are 139

expressed using the relevant laboratory’s LLOQ. Antibodies to HBsAg were measured by 140

radioimmunoassay only as part of the original study and expressed as mIU/mL. 141

Safety Endpoints. Safety endpoints and related periods of follow-up postvaccination 142

were as follows: rates of solicited injection site reactions (pain, erythema, swelling, axillary 143


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lymph node swelling) and solicited systemic reactions (fever, chills, headache, generalized 144

bodyache and/or muscle weakness, tiredness and/or decreased energy, nausea, vomiting, 145

diarrhea, and sore and/or swollen joints) at 0–24 hours, 24–72 hours, and 3–14 days; rates of 146

immediate reactions within 30 minutes; unsolicited adverse events (AEs) as spontaneously 147

reported within 14 days after Tdap-IPV injection; and serious adverse events (SAEs) at any time 148

during the study through 30 days after the last vaccination. The intensity of solicited local and 149

systemic reactions was classified as mild, moderate and severe based on magnitude (mild < 10 150

mm; moderate 10–34 mm and severe >35 mm of redness or swelling) and degree of interference 151

with daily activities for systemic AEs. Orally measured fever was classified as mild (38.0 ºC–38.9 152

ºC), moderate (39.0 ºC–39.9 ºC), or severe (≥40 ºC). Moderate and severe AEs were grouped 153

together in the analysis. 154

Immunogenicity Endpoints. Immunogenicity was measured by the proportion of 155

participants achieving seroprotective levels of antibodies ≥0.01 IU/mL and 0.1 IU/mL for 156

diphtheria and tetanus, and ≥1:8 dilution for poliovirus. For pertussis, rates of 4-fold increase in 157

antibody levels were calculated 1 month postvaccination. To examine immunologic interactions 158

between Tdap-IPV and HepB, geometric mean titers (GMTs) of antibodies and corresponding 159

seroprotection rates achieved for each Tdap-IPV antigen (not shown for pertussis) were 160

compared. For HepB vaccine, immunogenicity was measured by the proportion of participants 161

attaining ≥10 mIU/mL, the seroprotective hepatitis B antibody level. 162

Immunogenicity endpoints for all Tdap-IPV antigens were also evaluated at 3, 5, and 10 163

years postvaccination, as described above. Pertussis antibody levels were assessed against LLOQ 164

where antibody levels ≥LLOQ were considered seropositive. 165


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Statistical analysis. A sample size of 140 participants per treatment arm was calculated 166

to provide 90% power at a two-sided significance level of 5% to detect a difference in treatment 167

arms of 15% and allow for a 10% drop-out rate. The intended sample size was determined based 168

on antibody responses to pertussis antigens in prior studies using the two-sided equivalence 169

approach for the difference in two proportions (24). 170

No formal hypothesis was tested and no statistical testing was performed in this study. 171

Safety endpoints were summarized as the number and percentage of participants with a solicited 172

reaction or unsolicited AE tabulated by intensity and study group. Differences between groups in 173

response rates with 90% confidence intervals (CIs) were calculated for each AE at each time 174

point. The solicited AEs were considered clinically equivalent if the confidence interval on the 175

difference in the rates between groups was within the interval of –15% to +15%. For 176

immunogenicity endpoints, continuous variables were presented by summary statistics (mean, 177

standard deviation [SD], GMTs with 95% CI) and categorical variables by frequency 178

distributions (counts and percentages). Differences in anti-diphtheria, anti-tetanus, and anti-179

poliovirus seroprotection rates, and pertussis 4-fold increases were calculated with 90% CIs (data 180

not shown). For pertussis in the long-term follow-up, seropositivity (≥LLOQ) was presented by 181

descriptive statistics. 182

All participants who received study vaccine and had ≥1 valid postvaccination safety or 183

immunogenicity evaluation were included in the intent-to-treat (ITT) analysis set and analyzed 184

for safety and immunogenicity. All participants without a protocol deviation were included in the 185

per-protocol (PP) analysis set for immunogenicity analyses. 186

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RESULTS 188

Participants. Healthy participants (N=280) were randomized to Group 1 (n=145) or Group 2 189

(n=135). Nine participants terminated the study before completion (Figure 1). The groups were 190

balanced for age (mean 12.4 years for both Groups) and sex distribution (52.1% female in Group 191

1; 44.7% female in Group 2). Of the 277 participants available for immunogenicity assessments 192

in the original study, 274 (98.9%) provided serum samples at 1 month, 224 (80.9%) at 3 years, 193

225 (81.2%) at 5 years, and 174 (62.8%) at 10 years postvaccination. The participants who 194

contributed samples in the long-term follow-up were representative of the original study with 195

respect to age, sex, and baseline vaccine antigen immune responses (data not shown). 196

The first participant visit occurred on January 9, 1999 and the last participant visit 197

following vaccination was May 27, 2000. First and last participant visits, respectively, were 198

January 23, 2002 and October 14, 2002 for the 3-year sampling; February 18, 2004 and October 199

20, 2004 for the 5-year sampling; and March 24, 2009 and June 4, 2009 for the 10-year 200

sampling. 201

Safety results. Overall, the rates of AEs were comparable between groups. No 202

vaccination-related SAEs were reported and no safety concerns were identified. No consistent 203

increases in solicited reactions or unsolicited AEs were reported when Tdap-IPV and HepB with 204

coadministration. 205

Solicited reactions. Most solicited local reactions at the Tdap-IPV injection site were 206

mild and occurred within 0–24 hours postvaccination (Table 1). Pain was the most frequently 207

reported local reaction at 0–24 hours and was reported by almost all participants. In the 24–72 208

hour interval, reports of pain at the Tdap-IPV injection site were higher in Group 1 (58.3%) than 209

Group 2 (50.8%). By 3–14 days, the frequency of pain reports had diminished equally in both 210


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groups. A similar trend was observed for redness and swelling. Axillary lymph node swelling 211

was most frequently reported within 24–72 hours. Overall, the local AE rates at the Tdap-IPV 212

injection site were comparable between groups. 213

Solicited systemic reactions were mostly mild and more commonly reported in both 214

groups in the first 24 hours (Table 2). The most frequent reports in the first 24 hours were for 215

bodyache/muscle weakness and tiredness. At 24–72 hours, the frequency of systemic AE reports 216

decreased in both groups (ranging from 0 for vomiting to a maximum of 23.5% for headaches 217

and tiredness in Group 2). At 3–14 days, there was an apparent increase in the rate of headache, 218

diarrhea, nausea, and vomiting reports (ranging from 2.3% for vomiting in Group 2 to 40.3% for 219

headaches in Group 1). These events were equally distributed between groups and were not 220

considered to be directly related to the vaccination. Fever reports were rare in both groups: 3 in 221

each group within 0–24 hours; 4 in Group 1 and 2 in Group 2 within 24–72 hours. Rates of 222

solicited systemic reactions were numerically similar in both groups. 223

Unsolicited AEs. Unsolicited AEs were reported by approximately 60% of participants, 224

with comparable reporting at 61.8% in Group 1 and 58.3% in Group 2. Most unsolicited AEs 225

were mild, with onset in the first days after vaccination and were reported as unrelated to study 226

vaccine. These reports were not coded; however, the most common AEs reported were cold 227

symptoms/flu-like syndrome followed by stomach ache. Unsolicited AEs reported as definitely 228

related to vaccination were also equally distributed between Group 1 and 2 (8 per group). 229

Serious Adverse Events. Four SAEs were reported; all required hospitalization and none 230

was considered to be vaccination-related. One participant from each group experienced a fracture 231

(at 7 days postvaccination for one participant and 29 days postvaccination for the other [third 232

HepB dose)]. In addition, a Group 2 participant experienced appendicitis at 11 days after the 233


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first dose of HepB and Tdap-IPV, and a diabetic Group 2 participant experienced viral 234

gastroenteritis and unstable glycaemia 3 months after the second dose of HepB. 235

Immunogenicity. Seroprotection/seroresponse. At 1 month postvaccination, 236

seroprotection rates against diphtheria, tetanus, and poliomyelitis were comparable between 237

groups (Tables 3 and 4); all reached seroprotective antibody levels of ≥0.01 IU/mL for diphtheria 238

and tetanus, ≥1:8 for poliovirus types 1, 2, and 3, and (≥10 mIU/mL) for hepatitis B. All 239

participants achieved levels of ≥0.1 IU/mL for tetanus. For diphtheria, 98.6% of Group 1 240

participants and 100% of Group 2 participants achieved seroprotective levels of ≥0.1 IU/mL. 241

Pertussis antibody seroresponses 1 month after Tdap-IPV vaccination were comparable 242

between Groups 1 and 2 as measured by 4-fold increases: PT (Group 1=88.7% versus Group 243

2=86.4%), FHA (76.6% versus 72.7%), FIM (88.7% versus 90.8%), and PRN (95.8% versus 244

87.9%). No clinically relevant interference was observed with Tdap-IPV and HepB 245

coadministration. 246

Antibody geometric mean titers. Although high prevaccination tetanus, diphtheria, and 247

poliovirus antibody levels were observed, GMTs rose after vaccination indicating a booster 248

response (Table 5). Tetanus and diphtheria GMTs at 1 month after Tdap-IPV vaccination were 249

comparable whether the vaccine was given alone or with a dose of HepB. Poliovirus GMTs 250

achieved were high (Table 5). 251

Antibody persistence. Long-term antibody persistence was evaluated from blood samples 252

taken 3, 5, and 10 years after Tdap-IPV vaccination. Immunogenicity profiles were comparable 253

between groups for all endpoints and at all time points. For diphtheria, tetanus, and poliomyelitis, 254

seroprotection rates remained high for up to 10 years postvaccination (Tables 3 and 4). At 10 255

years, 100% of participants had anti-diphtheria antibody levels of ≥0.01 IU/mL, while 85.9% 256


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(Group 1=88.4%; Group 2=82.9%) maintained levels ≥0.1 IU/mL, adequate for long-term 257

protection (25). For tetanus, 100% of participants maintained levels ≥0.01 IU/mL at 10 years, 258

while 98.7% (Group 1=100%; Group 2=97.1%) maintained levels ≥0.1 IU/mL. All participants 259

maintained poliovirus seroprotective levels ≥ 1:8 for all 3 poliovirus types at all postvaccination 260

time periods. 261

After substantial increases at 1 month after vaccination, anti-diphtheria, anti-tetanus and 262

anti-poliovirus GMTs declined during the first 3 years (Table 5). At 10 years, diphtheria and 263

tetanus GMTs had returned to prevaccination levels. Anti-poliovirus GMT levels declined over 264

time, but remained above prevaccination levels for all 3 poliovirus types (Table 5). Anti-265

pertussis GMTs declined over time, with the largest decrease occurring in the first years 266

postvaccination (Figure 2). 267

Pertussis seropositivity was defined as ≥LLOQ for follow-up time points, and at 1 month 268

postvaccination, 100% of participants had detectable antibodies for each pertussis antigen (Table 269

6). Antibodies persisted at levels higher than prevaccination at 5 years, but returned to those 270

levels after 10 years for PT and FHA (Figure 2). Anti-PRN and anti-FIM antibody levels at 10 271

years were still above prevaccination levels. PT had the lowest percentage of participants with 272

detectable antibodies after 10 years (74.1%); the other three antigens were higher (96.5%–273

98.2%). 274

Results for immunogenicity outcomes were similar between the ITT and PP populations. 275

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DISCUSSION 277

Tdap-IPV is approved in numerous countries around the world as a booster vaccine in persons 3 278

years of age and older. This study examined coadministration of Tdap-IPV with HepB in 279

adolescents and the persistence of Tdap-IPV antibodies for up to 10 years. The solicited AE rates 280

were generally comparable to those observed in adolescents and adults who were vaccinated 281

with a single dose of a Tdap or Tdap-Polio vaccine (26). AE rates were comparable between 282

study groups. There were no consistent increases in rates of solicited reactions or unsolicited 283

AEs when Tdap-IPV and HepB were coadministered at separate injection sites, except for pain 284

reports at 24-72 hours postvaccination. One month after the Tdap-IPV vaccination, immune 285

responses to all antigens were robust. 286

Long-term immunogenicity results from this study are consistent with results from a 287

pooled analysis of 10-year immunogenicity data from three clinical trials conducted in 288

adolescents and adults (19). In that analysis, 99.3% of adolescents had protective levels of 289

antibodies against diphtheria and tetanus and seropositivity to 1 or more pertussis antigens 10 290

years after their booster dose of Tdap. Adolescents in one of the studies included in the pooled 291

analysis also received HepB vaccine, which did not appear to affect immunogenicity of 292

diphtheria, tetanus, and pertussis, similar to the results presented here. 293

While pertussis protective levels have not yet been clearly defined, previous publications 294

have defined minimal long-term protective levels as greater than the LLOQ value (14, 27). For 295

all pertussis antigens at 1 month postvaccination, all participants achieved antibody levels that 296

were ≥LLOQ; at 10 years postvaccination, between 74.1% and 98.2% of participants (2 groups 297

combined) maintained detectable antibody levels. Further, all vaccinees maintained 298

seroprotective levels for diphtheria, tetanus and all 3 poliovirus serotypes at 10 years after Tdap-299


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IPV administration. Thus, the long-term antibody profile suggests seroprotection against 300

diphtheria, tetanus and poliomyelitis is maintained for at least 10 years after booster adolescent 301

vaccination. 302

The study had some limitations. The study was powered to evaluate immunogenicity and 303

rare AEs or SAEs may not have been detected. Safety was assessed for 14 days after each 304

vaccination (except for SAEs, which were collected at any time through 30 days after the last 305

vaccination), but was not collected throughout the 10-year follow-up. Only 62.8% of participants 306

could be assessed at the 10-year follow-up and not all participants could be assessed at all 307

timepoints. The determination of prior exposure to pertussis disease or pertussis vaccination was 308

based on participants recall only and was not verified from medical records. 309

When given alone or concurrently with HepB, the results demonstrated that Tdap-IPV is 310

safe and immunogenic in 11- to 14-year-old adolescents. Clinically relevant immunologic 311

interactions did not occur when Tdap-IPV and HepB were given concurrently, which provides 312

evidence for a recommendation that the vaccines can be administered simultaneously. This 313

strategy would eliminate the need for an additional medical visit and facilitate cost-effective 314

vaccination. This approach would also improve the ability of immunization programs to meet 315

target goals for vaccine coverage. 316

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ACKNOWLEDGMENTS 318

We thank the Study Investigators and the staff at University of Manitoba. Robert Lersch of 319

Sanofi Pasteur reviewed and edited the manuscript. 320

321

FUNDING AND ROLE OF THE SPONSOR: This study was funded by Sanofi Pasteur, 322

which also contributed to study design, data collection, analysis and interpretation, review of 323

manuscript and decision to publish. 324

325

AUTHOR DISCLOSURES: J. Embree and B. Law had no conflicts of interest to declare. 326

T.Voloshen and A.Tomovici are employees of Sanofi Pasteur. 327

328

AUTHOR CONTRIBUTIONS: J.Embree and B. Law participated in study design and data 329

acquisition. T.Voloshen and A.Tomovici participated in study design, and acquisition and 330

interpretation of data. All authors helped write, edit or review the manuscript. 331

332

333

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REFERENCES 335

1. Centers for Disease Control and Prevention (CDC). 2011. Notifiable Diseases and 336

Mortality Tables. MMWR Morb. Mortal. Wkly. Rep. 59:1690-1703. 337

2. Sin MA, Zenke R, Ronckendorf R, Littmann M, Jorgensen P, Hellenbrand W. 2009. 338

Pertussis outbreak in primary and secondary schools in Ludwigslust, Germany demonstrating the 339

role of waning immunity. Pediatr. Infect. Dis. J. 28:242-244. 340

3. Edwards KM. 2005. Overview of pertussis: focus on epidemiology, sources of infection, 341

and long term protection after infant vaccination. Pediatr. Infect. Dis. J. 24:S104-108. 342

4. World Health Organization. 2010. Pertussis vaccines: WHO position paper. Wkly. 343

Epidemiol. Rec. 40:385-400. 344

5. Poolman JT, Hallander H, Halperin SA. 2011. Pertussis vaccines: where to now? Expert 345

Rev. Vaccines. 10:1497-1500. 346

6. Wood N, McIntyre P. 2008. Pertussis: review of epidemiology, diagnosis, management and 347

prevention. Paediatr. Respir. Rev. 9:201-211. 348

7. Centers for Disease Control and Prevention (CDC). 2012. Pertussis Epidemic — 349

Washington, 2012. MMWR Morb. Mortal. Wkly. Rep. 61:517-522. 350


.org/D

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http://cvi.asm.org/

19

8. Centers for Disease Control and Prevention (CDC). 2012. Notifiable diseases and 351

mortality tables. MMWR Morb. Mortal. Wkly. Rep. 61:ND635-ND638. 352

9. Kowalzik F, Barbosa AP, Fernandes VR, Carvalho PR, Avila-Aguero ML, Goh DY, 353

Goh A, de Miguel JG, Moraga F, Roca J, Campins M, Huang M, Quian J, Riley N, Beck D, 354

Verstraeten T. 2007. Prospective multinational study of pertussis infection in hospitalized 355

infants and their household contacts. Pediatr. Infect. Dis. J. 26:238-242. 356

10. de Greeff SC, Mooi FR, Westerhof A, Verbakel JM, Peeters MF, Heuvelman CJ, 357

Notermans DW, Elvers LH, Schellekens JF, de Melker HE. 2010. Pertussis disease burden 358

in the household: how to protect young infants. Clin. Infect. Dis. 50:1339-1345. 359

11. Coudeville L, van Rie A, Andre P. 2008. Adult pertussis vaccination strategies and their 360

impact on pertussis in the United States: evaluation of routine and targeted (cocoon) strategies. 361

Epidemiol. Infect. 136:604-620. 362

12. National Advisory Committee on Immunization (NACI). 2000. Statement on alternate 363

adolescent schedule for hepatitis B vaccine (ACS-5). An Advisory Committee Statement (ACS). 364

Can. Commun. Dis. Rep. 26:19-20. 365

13. McIntyre PB, Turnbull FM, Egan AM, Burgess MA, Wolter JM, Schuerman LM. 366

2004. High levels of antibody in adults three years after vaccination with a reduced antigen 367

content diphtheria-tetanus-acellular pertussis vaccine. Vaccine. 23:380-385. 368


.org/D

ownloaded from

http://cvi.asm.org/

20

14. Edelman KJ, He Q, Makinen JP, Haanpera MS, Tran Minh NN, Schuerman L, Wolter 369

J, Mertsola JA. 2004. Pertussis-specific cell-mediated and humoral immunity in adolescents 3 370

years after booster immunization with acellular pertussis vaccine. Clin. Infect. Dis. 39:179-185. 371

15. Barreto L, Guasparini R, Meekison W, Noya F, Young L, Mills E. 2007. Humoral 372

immunity 5 years after booster immunization with an adolescent and adult formulation combined 373

tetanus, diphtheria, and 5-component acellular pertussis vaccine. Vaccine. 25:8172-8179. 374

16. Mertsola J, Van Der Meeren O, He Q, Linko-Parvinen A, Ramakrishnan G, 375

Mannermaa L, Soila M, Pulkkinen M, Jacquet JM. 2010. Decennial administration of a 376

reduced antigen content diphtheria and tetanus toxoids and acellular pertussis vaccine in young 377

adults. Clin. Infect. Dis. 51:656-662. 378

17. McIntyre PB, Burgess MA, Egan A, Schuerman L, Hoet B. 2009. Booster vaccination 379

of adults with reduced-antigen-content diphtheria, Tetanus and pertussis vaccine: 380

immunogenicity 5 years post-vaccination. Vaccine. 27:1062-1066. 381

18. Booy R, Van der Meeren O, Ng SP, Celzo F, Ramakrishnan G, Jacquet JM. 2010. A 382

decennial booster dose of reduced antigen content diphtheria, tetanus, acellular pertussis vaccine 383

(Boostrix) is immunogenic and well tolerated in adults. Vaccine. 29:45-50. 384

19. Tomovici A, Barreto L, Zickler P, Meekison W, Noya F, Voloshen T, Lavigne P. 2012. 385

Humoral immunity 10 years after booster immunization with an adolescent and adult formulation 386


.org/D

ownloaded from

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21

combined tetanus, diphtheria, and 5-component acellular pertussis vaccine. Vaccine. 30:2647-387

2653. 388

20. Bailleux F, Coudeville L, Kolenc-Saban A, Bevilacqua J, Barreto L, Andre P. 2008. 389

Predicted long-term persistence of pertussis antibodies in adolescents after an adolescent and 390

adult formulation combined tetanus, diphtheria, and 5-component acellular pertussis vaccine, 391

based on mathematical modeling and 5-year observed data. Vaccine. 26:3903-3908. 392

21. Adacel®

-Polio Product Monograph. Tetanus toxoid, reduced diphtheria toxoid and acellular 393

pertussis vaccine adsorbed combined with inactivated poliomyelitis vaccine. 2013. Sanofi 394

Pasteur Ltd., Toronto, Ontario, Canada. 395

22. Recombivax HB® Product Monograph. Hepatitis B vaccine (recombinant). 2012. Merck 396

Canada Inc., Kirkland, Quebec, Canada. 397

23. World Health Organization, Department of Immunization, Vaccines and Biologicals. 398

2009. The Immunological Basis for Immunization Series. Module 4: Pertussis - Update 2009. 399

World Health Organization, Geneva, Switzerland 400

24. Farrington C, Manning G. 1990. Test statistics and sample size formulae for comparative 401

binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. 402

Stat.Med. 9:1447-1454. 403


.org/D

ownloaded from

http://cvi.asm.org/

22

25. World Health Organization, Department of Immunization, Vaccines and Biologicals. 404

2009. The Immunological Basis for Immunization Series. Module 2: Diphtheria - Update 2009. 405

World Health Organization, Geneva, Switzerland 406

26. Halperin SA, Smith B, Russell M, Scheifele D, Mills E, Hasselback P, Pim C, Meekison 407

W, Parker R, Lavigne P, Barreto L. 2000. Adult formulation of a five component acellular 408

pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus 409

vaccine is safe and immunogenic in adolescents and adults. Pediatr. Infect. Dis. J. 19:276-283. 410

27. Storsaeter J, Hallander HO, Gustafsson L, Olin P. 1998. Levels of anti-pertussis 411

antibodies related to protection after household exposure to Bordetella pertussis. Vaccine. 412

16:1907-1916. 413

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Table 1. Summary of local adverse events reported at 0-24 hours and 24-72 hours 416

postvaccination (ITT analysis set) 417

Event and intensity

Group 1a

(N = 144)

n (%)

Group 2b

(N = 132)

n (%)

Differencec

% (95% CI)

0-24 hours postvaccination

Redness

Any intensity

Moderate or severe intensity

36 (25.0)

9 (6.3)

30 (22.7)

12 (9.1)

-2.3 (-10.7, 6.2)

2.8 (-2.4, 8.1)

Swelling

Any intensity


31 (21.5)

22 (15.3)

27 (20.5)

23 (17.4)

-1.1 (-9.1, 7.0)

2.1 (-5.2, 9.5)

Pain

Any intensity


138 (95.8)

55 (38.2)

126 (95.5)

52 (39.4)

-0.4 (-4.4, 3.7)

1.2 (-8.5, 10.9)

Lymph node swelling

Any intensity


7 (4.9)

1 (0.7)

3 (2.3)

2 (1.5)

-2.6 (-6.2, 1.1)

0.8 (-1.3, 2.9)


Redness

Any intensity


22 (15.3)

4 (2.8)

19 (14.4)

9 (6.8)

-0.9 (-7.9, 6.2)

4.0 (-0.2, 8.3)

Swelling

Any intensity


18 (12.5)

10 (6.9)

17 (12.9)

14 (10.6)

0.4 (-6.2, 7.0)

3.7 (-2.0, 9.3)

Pain

Any intensity


84 (58.3)

7 (4.9)

67 (50.8)

10 (7.6)

-7.6 (-17.4, 2.3)

2.7 (-2.1, 7.5)


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Event and intensity

Group 1a

(N = 144)

n (%)

Group 2b

(N = 132)

n (%)

Differencec

% (95% CI)

Lymph node swelling

Any intensity


7 (4.9)

1 (0.7)

5 (3.8)

1 (0.8)

-1.1 (-5.1, 2.9)

0.1 (-1.6, 1.7)

aGroup1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. 418 bGroup 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. 419 cDifference = Group 2 rate – Group 1 rate. 420 ITT, intent-to-treat; CI, confidence interval. 421

422


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Table 2. Summary of systemic adverse events (ITT analysis set) 423

Event and intensity

Group 1a

(N = 144)

n (%)

Group 2b

(N = 132)

n (%)

Differencec

% (95% CI)


Fever

Any intensity


3 (2.1)

0

3 (2.3)

1 (0.8)

0.2 (-2.7, 3.1)

0.8 (-0.5, 2.0)

Chills

Any intensity


25 (17.4)

6 (4.2)

21 (15.9)

3 (2.3)

-1.5 (-8.8, 5.9)

-1.9 (-5.4, 1.6)

Headache

Any intensity


51 (35.4)

10 (6.9)

47 (35.6)

8 (6.1)

0.2 (-9.3, 9.7)

-0.9 (-5.8, 4.0)

Nausea

Any intensity


20 (13.9)

5 (3.5)

22 (16.7)

4 (3.0)

2.8 (-4.4, 9.9)

-0.4 (-4.0, 3.1)

Vomiting

Any intensity


2 (1.4)

1 (0.7)

0

0

-1.4 (-3.0, 0.2)

-0.7 (-1.8, 0.4)

Diarrhea

Any intensity


3 (2.1)

0

7 (5.3)

1 (0.8)

3.2 (-0.5, 7.0)

0.8 (-0.5, 2.0)

Bodyache/muscle weakness

Any intensity


59 (41.0)

12 (8.3)

50 (37.9)

17 (12.9)

-3.1 (-12.8, 6.6)

4.5 (-1.6, 10.7)

Tiredness

Any intensity


58 (40.3)

7 (4.9)

53 (40.2)

12 (9.1)

-0.1 (-9.8, 9.6)

4.2 (-0.8, 9.3)


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Event and intensity

Group 1a

(N = 144)

n (%)

Group 2b

(N = 132)

n (%)

Differencec

% (95% CI)

Sore joints

Any intensity


26 (18.1)

6 (4.2)

27 (20.5)

6 (4.5)

2.4 (-5.4, 10.2)

0.4 (-3.7, 4.4)


Fever

Any intensity


4 (2.8)

0

2 (1.5)

0

-1.3 (-4.1, 1.6)

NA

Chills

Any intensity


11 (7.6)

1 (0.7)

9 (6.8)

0

-0.8 (-6.0, 4.3)

-0.7 (-1.8, 0.4)

Headache

Any intensity


30 (20.8)

2 (1.4)

31 (23.5)

1 (0.8)

2.7 (-5.6, 10.9)

-0.6 (-2.7, 1.4)

Nausea

Any intensity


9 (6.3)

1 (0.7)

15 (11.4)

2 (1.5)

5.1 (-0.5, 10.8)

0.8 (-1.3, 2.9)

Vomiting

Any intensity


0

0

0

0

NA

NA

Diarrhea

Any intensity


7 (4.9)

0

4 (3.0)

0

-1.8 (-5.7, 2.0)

NA


Any intensity


24 (16.7)

4 (2.8)

23 (17.4)

2 (1.5)

0.8 (-6.7, 8.2)

-1.3 (-4.1, 1.6)


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Event and intensity

Group 1a

(N = 144)

n (%)

Group 2b

(N = 132)

n (%)

Differencec

% (95% CI)

Tiredness

Any intensity


31 (21.5)

3 (2.1)

31 (23.5)

3 (2.3)

2.0 (-6.3, 10.3)

0.2 (-2.7, 3.1)

Sore joints

Any intensity


15 (10.4)

6 (4.2)

14 (10.6)

0

0.2 (-5.9, 6.3)

-4.2 (-6.9, -1.4)

3-14 days postvaccination

Fever

Any intensity


3 (2.1)

1 (0.7)

7 (5.3)

0

3.2 (-0.5, 7.0)

-0.7 (-1.8, 0.4)

Chills

Any intensity


26 (18.1)

3 (2.1)

17 (12.9)

2 (1.5)

-5.2 (-12.3, 2.0)

-0.6 (-3.2, 2.1)

Headache

Any intensity


58 (40.3)

18 (12.5)

52 (39.4)

12 (9.1)

-0.9 (-10.6, 8.8)

-3.4 (-9.5, 2.7)

Nausea

Any intensity


30 (20.8)

13 (9.0)

17 (12.9)

5 (3.8)

-8.0 (-15.3, -0.6)

-5.2 (-10.0, -0.5)

Vomiting

Any intensity


6 (4.2)

1 (0.7)

3 (2.3)

1 (0.8)

-1.9 (-5.4, 1.6)

0.1 (-1.6, 1.7)

Diarrhea

Any intensity


23 (16.0)

6 (4.2)

20 (15.2)

2 (1.5)

-0.8 (-8.0, 6.4)

-2.7 (-5.9, 0.6)


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Event and intensity

Group 1a

(N = 144)

n (%)

Group 2b

(N = 132)

n (%)

Differencec

% (95% CI)


Any intensity


21 (14.6)

7 (4.9)

28 (21.2)

5 (3.8)

6.6 (-1.0, 14.2)

-1.1 (-5.1, 2.9)

Tiredness

Any intensity


39 (27.1)

14 (9.7)

30 (22.7)

8 (6.1)

-4.4 (-12.9, 4.2)

-3.7 (-9.0, 1.6)

Sore joints

Any intensity


21 (14.6)

7 (4.9)

12 (9.1)

5 (3.8)

-5.5 (-11.8, 0.9)

-1.1 (-5.1, 2.9)

aGroup1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. 424 bGroup 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. 425 cDifference = Group 2 rate – Group 1 rate. 426 ITT, intent-to-treat; CI, confidence interval; NA, not applicable. 427 428


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Table 3. Diphtheria and tetanus seroprotection rates as measured by the proportion of participants with antibody levels ≥ 0.01 IU/mL 429

or ≥ 0.1 IU/mL prevaccination and at 1 month and 3, 5, and 10 years postvaccination (ITT analysis set) 430

Group 1a Group 2b

≥ 0.01 IU/mL ≥ 0.1 IU/mL ≥ 0.01 IU/mL ≥ 0.1 IU/mL

Antigen and visit n/N % (95% CI) % (95% CI) n/N % (95% CI) % (95% CI)

Diphtheria

Prevaccination

1 month

3 years

5 years

10 years

142/144

142/142

110/110

108/110

86/86

98.6 (95.1, 99.8)

100 (97.4, 100)

100 (96.7, 100)

98.2 (93.6, 99.8)

100 (95.8, 100)

81.9 (74.7, 87.9)

98.6 (95.0, 99.8)

91.8 (85.0, 96.2)

76.4 (67.3, 83.9)

88.4 (79.7, 94.3)

132/132

132/132

98/100

96/96

70/70

83.3 (75.9, 89.3)

100 (97.2, 100)

90.0 (82.4, 95.1)

76.0 (66.3, 84.2)

82.9 (72.0, 90.8)

100 (97.2, 100)

100 (97.2, 100)

98.0 (93.0, 99.8)

100 (96.2, 100)

100 (94.9, 100)

Tetanus

Prevaccination

1 month

3 years

5 years

10 years

144/144

142/142

109/109

107/107

80/80

100 (97.5, 100)

100 (97.4, 100)

100 (96.7, 100)

100 (96.6, 100)

100 (95.5, 100)

99.3 (96.2, 100)

100 (97.4, 100)

100 (96.7, 100)

100 (96.6, 100)

100 (95.5, 100)

132/132

132/132

100/100

96/96

69/69

100 (97.2, 100)

100 (97.2, 100)

100 (96.4, 100)

99.0 (94.3, 100)

97.1 (89.9, 99.6)

100 (97.2, 100)

100 (97.2, 100)

100 (96.4, 100)

100 (96.2, 100)

100 (94.8, 100)

aGroup 1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. 431 bGroup 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. 432 ITT, intent-to-treat; n, number of participants with result; N, number of participants with available data; CI, confidence interval. 433


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Table 4. Seroprotection rates for poliovirus (≥ 1:8 dilution) and hepatitis B (≥ 10 mIU/mL) 434

antigens prevaccination and at 1 month and 3, 5, and 10 years postvaccination (ITT analysis set) 435

Group 1a Group 2b

Antigen and visit n/N % (95% CI) n/N % (95% CI)

Poliovirus serotype 1

Prevaccination

1 month

3 years

5 years

10 years

138/144

142/142

116/116

118/118

91/91

95.8 (91.2, 98.5)

100 (97.4, 100)

100 (96.9, 100)

100 (96.9, 100)

100 (96.0, 100)

124/132

132/132

107/107

106/106

82/82

93.9 (88.4, 97.3)

100 (97.2, 100)

100 (96.6, 100)

100 (96.6, 100)

100 (95.6, 100)


Prevaccination

1 month

3 years

5 years

10 years

143/144

142/142

116/116

118/118

91/91

99.3 (96.2, 100)

100 (97.4, 100)

100 (96.9, 100)

100 (96.9, 100)

100 (96.0, 100)

132/132

132/132

106/106

106/106

82/82

100 (97.2, 100)

100 (97.2, 100)

100 (96.6, 100)

100 (96.6, 100)

100 (95.6, 100)


Prevaccination

1 month

3 years

5 years

10 years

137/144

142/142

116/116

118/118

90/90

95.1 (90.2, 98)

100 (97.4, 100)

100 (96.9, 100)

100 (96.9, 100)

100 (96.0, 100)

126/132

132/132

107/107

106/106

80/80

95.5 (90.4, 98.3)

100 (97.2, 100)

100 (96.6, 100)

100 (96.6, 100)

100 (95.5, 100)

Hepatitis Bc 116/118 100 (96.9, 100) 123/123 100 (97.1, 100)

aGoup1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. 436 bGroup 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. 437 cHepatitis B data are from samples collected 1 month after dose 3 only. 438 ITT, intent-to-treat; n, number of participants with result; N, number of participants with available data; CI, 439 confidence interval. 440


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Table 5. Geometric mean titers for diphtheria (IU/mL), tetanus (IU/mL), and poliovirus (≥ 1:8 dilution) antigens prevaccination and 441

at 1 month and 3, 5, and 10 years postvaccination (ITT analysis set) 442

Group 1a Group 2b Combined Groups 1 and 2

Antigen and visit N GMT (95% CI) N GMT (95% CI) N GMT (95% CI)

Diphtheria

Prevaccination

1 month

3 years

5 years

10 years

144

142

110

110

86

0.30 (0.24, 0.39)

5.12 (4.21, 6.21)

0.51 (0.41, 0.63)

0.22 (0.17, 0.27)

0.34 (0.26, 0.45)

132

132

100

96

70

0.39 (0.31, 0.49)

5.90 (4.97, 7.00)

0.57 (0.44, 0.74)

0.23 (0.18, 0.28)

0.30 (0.23, 0.39)

276

274

210

206

156

0.34 (0.29, 0.40)

5.48 (4.81, 6.24)

0.54 (0.45, 0.63)

0.22 (0.19, 0.26)

0.32 (0.27, 0.39)

Tetanus

Prevaccination

1 month

3 years

5 years

10 years

144

142

109

107

80

0.58 (0.51, 0.65)

7.64 (6.79, 8.59)

1.34 (1.19, 1.50)

0.89 (0.77, 1.04)

0.66 (0.54, 0.79)

132

132

100

96

69

0.61 (0.54, 0.69)

6.95 (6.12, 7.90)

1.31 (1.15, 1.50)

0.94 (0.80, 1.10)

0.71 (0.58, 0.87)

276

274

209

203

149

0.59 (0.54, 0.64)

7.30 (6.70, 7.95)

1.33 (1.22, 1.45)

0.92 (0.82, 1.02)

0.68 (0.59, 0.78)


Prevaccination

1 month

3 years

5 years

10 years

144

142

116

118

91

79.22 (60.01, 104.6)

40520 (30950, 53040)

2289 (1749, 2996)

586.1 (475.4, 722.4)

519.9 (411.1, 657.4)

132

132

107

106

82

87.52 (65.05, 117.8)

24600 (19460, 31100)

1692 (1264, 2265)

502.0 (410.7, 613.8)

514.2 (412.0, 641.6)

276

274

223

224

173

83.09 (67.92, 101.6)

31860 (26590, 38180)

1980 (1625, 2412)

544.7 (471.3, 629.5)

517.2 (440.5, 607.2)


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Antigen and visit N GMT (95% CI) N GMT (95% CI) N GMT (95% CI)


Prevaccination

1 month

3 years

5 years

10 years

144

142

116

118

91

158.65 (129.50, 194.36)

53135 (41590, 67883)

5185.2 (3952.8, 6801.7)

1232.1 (966.53, 1570.7)

740.80 (580.47, 945.42)

132

132

106

106

82

177.06 (147.94, 211.91)

33367 (27344, 40717)

4512.8 (3375.6, 6033.2)

1114.9 (894.97, 1388.8)

671.03 (521.63, 863.22)

276

274

222

224

173

167.21 (145.99, 191.51)

42466 (36168, 49860)

4852.5 (3984.9, 5908.9)

1175.2 (997.72, 1384.2)

706.87 (594.19, 840.91)


Prevaccination

1 month

3 years

5 years

10 years

144

142

116

118

90

48.64 (38.32, 61.75)

230900 (174400, 305700)

5827 (4431, 7663)

846.0 (664.4, 1077)

758.3 (584.7, 983.6)

132

132

107

106

80

45.97 (36.95, 57.20)

136700 (104900, 178200)

5412 (4021, 7283)

825.3 (642.0, 1061)

782.8 (583.6, 1050)

276

274

223

224

170

47.35 (40.28, 55.65)

179400 (147600, 217900)

5624 (4605, 6869)

836.1 (703.4, 993.9)

769.7 (634.6, 933.7)

aGoup1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. 443 bGroup 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. 444 GMT, geometric mean titer; ITT, intent-to-treat; CI, confidence interval. 445

446


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Table 6. Seropositivity rates for pertussis antigens (≥ LLOQ) prevaccination and at 1 month and 3, 5, and 10 years postvaccination 447

(ITT analysis set) 448


Antigen and visit n/N % (95% CI) n/N % (95% CI) n/N % (95% CI)

PT

Prevaccination

1 month

3 years

5 years

10 years

121/144

142/142

107/111

114/116

63/88

84.0 (77.0, 89.6)

100 (97.4, 100)

96.4 (91.0, 99.0)

98.3 (93.9, 99.8)

71.6 (61.0, 80.7)

105/132

132/132

100/104

97/103

60/78

79.5 (71.7, 86.1)

100 (97.2, 100)

96.2 (90.4, 98.9)

94.2 (87.8, 97.8)

76.9 (66.0, 85.7)

226/276

274/274

207/215

211/219

123/166

81.9 (76.8, 86.2)

100 (98.7, 100)

96.3 (92.8, 98.4)

96.3 (92.9, 98.4)

74.1 (66.7, 80.6)

FHA

Prevaccination

1 month

3 years

5 years

10 years

142/143

142/142

114/114

116/116

89/90

99.3 (96.2, 100)

100 (97.4, 100)

100 (96.8, 100)

100 (96.9, 100)

98.9 (94.0, 100)

130/132

132/132

104/104

102/102

78/80

98.5 (94.6, 99.8)

100 (97.2, 100)

100 (96.5, 100)

100 (96.4, 100)

97.5 (91.3, 99.7)

272/275

274/274

218/218

218/218

167/170

98.9 (96.8, 99.8)

100 (98.7, 100)

100 (98.3, 100)

100 (98.3, 100)

98.2 (94.9, 99.6)

PRN

Prevaccination

1 month

3 years

5 years

10 years

115/144

142/142

113/114

114/116

86.90

79.9 (72.4, 86.1)

100 (97.4, 100)

99.1 (95.2, 100)

98.3 (93.9, 99.8)

95.6 (89.0, 98.8)

108/132

132/132

104/104

102/102

78/80

81.8 (74.2, 88.0)

100 (97.2, 100)

100 (96.5, 100)

99.0 (94.7, 100)

97.5 (91.3, 99.7)

223/276

274/274

217/218

215/218

164/170

80.8 (75.6, 85.3)

100 (98.7, 100)

99.5 (97.5, 100)

98.6 (96.0, 99.7)

96.5 (92.5, 98.7)


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Antigen and visit n/N % (95% CI) n/N % (95% CI) n/N % (95% CI)

FIM

Prevaccination

1 month

3 years

5 years

10 years

113/143

142/142

113/114

115/115

87/90

79.0 (71.4, 85.4)

100 (97.4, 100)

99.1 (95.2, 100)

100 (96.8, 100)

96.7 (90.6, 99.3)

113/131

132/132

103/104

101/103

78/80

86.3 (79.2, 91.6)

100 (97.2, 100)

99.0 (94.8, 100)

98.1 (93.2, 99.8)

97.5 (91.3, 99.7)

226/274

274/274

216/218

216/218

165/170

82.5 (77.5, 86.8)

100 (98.7, 100)

99.1 (96.7, 99.9)

99.1 (96.7, 99.9)

97.1 (93.3, 99.0)

aGoup1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. 449 bGroup 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. 450 ITT, intent-to-treat; n, number of participants with result; N, number of participants with available data; CI, confidence interval; PT, pertussis toxin; FHA, 451 filamentous hemagglutinin; PRN, pertactin; FIM, fimbrae 2 and 3. 452 453


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FIGURE LEGENDS 454

Figure 1. Participant disposition. AE, adverse event; ITT, intent-to-treat; PP, per-protocol. 455

456

Figure 2. Reverse cumulative distribution curves of antibody responses to pertussis antigens. 457

Reverse cumulative distribution curves for antibodies to (A) PT (LLOQ, 4-5 EU/mL), (B), FHA 458

(LLOQ, 3 EU/mL), (C) PRN (LLOQ, 3-4 EU/mL), and (D) FIM (LLOQ, 4-17 EU/mL) are 459

shown for samples collected prevaccination (black lines) and at 1 month (brown lines), 3 years 460

(dark blue lines), 5 years (light blue lines), and 10 years (red lines) postvaccination are shown. 461

PT, pertussis toxin; FHA, filamentous hemagglutinin; PRN, pertactin; FIM, fimbriae 2 and 3; 462

EU, ELISA units; LLOQ, lower limit of quantitation. 463

464

465


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Participants enrolled

N = 280

Allocated to Group 1

TdcP-IPV, HepB

N = 145

1 did not receive study vaccine

3 discontinued from study:

• Voluntary withdrawal

not due to AE (n=2)

• Other reason (n=1)

144 in ITT analysis set

118 in PP analysis set

142 completed vaccination

116 completed 3-year follow-up



Allocated to Group 2

TdcP-IPV+HepB

N = 135

2 did not receive study vaccine

6 discontinued from study:

• Voluntary withdrawal

not due to AE (n=6)

132 in ITT analysis set

123 in PP analysis set

129 completed vaccination



83 completed 10-year follow-up 466

467


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468

469


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