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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
6
Running Title: Adacel-Polio plus HepB booster in adolescents 7
8
Joanne Embreea, Barbara Law
a1, Tim Voloshen
b, Antigona Tomovici
c# 9
10
aUniversity of Manitoba, Winnipeg, MB, Canada 11
bSanofi Pasteur, Swiftwater, PA, USA 12
cSanofi Pasteur, Toronto, ONT, Canada 13
14
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
39
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Keywords: combination vaccines; adolescent booster; safety; immunogenicity; antibody 40
persistence; long-term follow-up 41
42
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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
75
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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
187
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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
276
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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
317
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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
334
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and long term protection after infant vaccination. Pediatr. Infect. Dis. J. 24:S104-108. 342
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8. Centers for Disease Control and Prevention (CDC). 2012. Notifiable diseases and 351
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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
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15. Barreto L, Guasparini R, Meekison W, Noya F, Young L, Mills E. 2007. Humoral 372
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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
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combined tetanus, diphtheria, and 5-component acellular pertussis vaccine. Vaccine. 30:2647-387
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based on mathematical modeling and 5-year observed data. Vaccine. 26:3903-3908. 392
21. Adacel®
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22. Recombivax HB® Product Monograph. Hepatitis B vaccine (recombinant). 2012. Merck 396
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2009. The Immunological Basis for Immunization Series. Module 4: Pertussis - Update 2009. 399
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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
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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
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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
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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)
24-72 hours postvaccination
Redness
Any intensity
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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)
0-24 hours postvaccination
Fever
Any intensity
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe intensity
2 (1.4)
1 (0.7)
0
0
-1.4 (-3.0, 0.2)
-0.7 (-1.8, 0.4)
Diarrhea
Any intensity
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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)
24-72 hours postvaccination
Fever
Any intensity
Moderate or severe intensity
4 (2.8)
0
2 (1.5)
0
-1.3 (-4.1, 1.6)
NA
Chills
Any intensity
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe intensity
0
0
0
0
NA
NA
Diarrhea
Any intensity
Moderate or severe intensity
7 (4.9)
0
4 (3.0)
0
-1.8 (-5.7, 2.0)
NA
Bodyache/muscle weakness
Any intensity
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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)
Bodyache/muscle weakness
Any intensity
Moderate or severe 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
Moderate or severe 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
Moderate or severe 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)
Poliovirus serotype 2
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)
Poliovirus serotype 3
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)
Poliovirus serotype 1
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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Group 1a Group 2b Combined Groups 1 and 2
Antigen and visit N GMT (95% CI) N GMT (95% CI) N GMT (95% CI)
Poliovirus serotype 2
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)
Poliovirus serotype 3
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
Group 1a Group 2b Combined Groups 1 and 2
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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Group 1a Group 2b Combined Groups 1 and 2
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
118 completed 5-year follow-up
91 completed 10-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
108 completed 3-year follow-up
107 completed 5-year follow-up
83 completed 10-year follow-up 466
467
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