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Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Diphtheria, tetanus and poliovirus antibody persistence 5 years after

vaccination of pre-schoolers with two different diphtheria, tetanus
and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and
immune responses to a booster dose of DTaP-IPV
Vincent Gajdos a,b , Emmanuel Vidor c , Patrick Richard d , Clément Tran d ,
Christine Sadorge d,∗
a
Paediatric Department, Hôpital Antoine Béclère, Hôpitaux Universitaires Paris-Sud, 157 Rue de la Porte de Trivaux, 92140 Clamart, France
b
Université Paris Sud, Le Kremlin Bicêtre, Orsay France
c
Sanofi Pasteur SA, 2 avenue Pont Pasteur, 69367 Lyon Cedex 07, France
d
Sanofi Pasteur MSD, 162 avenue Jean Jaurès, CS 50712, 69367 Lyon Cedex 07, France

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: This follow-up study assessed the 5-year persistence of vaccine-induced antibodies (Td-IPV
Received 14 November 2014 or DT-IPV) and the immune response to a booster dose of DTaP-IPV.
Received in revised form 1 June 2015 Methods: This was an open-label, parallel-group (two arms), multicentre trial performed at 44 study
Accepted 4 June 2015
sites in France. Children aged 11–13 years, of either sex, who received Td-IPV (Revaxis® ) and DT-IPV (DT
Available online xxx
Polio® ) vaccines at 6 years of age in one previous open-label trial with no further vaccination against
diphtheria, tetanus, pertussis or poliomyelitis, were enrolled. All participants received a single intramus-
Keywords:
cular booster dose (0.5 mL) of DTaP-IPV vaccine (Tetravac-Acellulaire® ). Study endpoints were based on
Vaccines
Booster response
antibody persistence and post-booster immune responses. Safety was monitored throughout the study.
Td-IPV Descriptive statistics were used for all analyses.
DT-IPV Results: Of the 758 children included in the previous study, 274 were included in this follow-up study;
DTaP-IPV 129 had previously been vaccinated with Td-IPV, and 145 had previously received DT-IPV. At least 96.5%
Antibody persistence of participants in both groups presented an anti-diphtheria and anti-tetanus concentration ≥0.01 IU/mL,
Safety and anti-poliovirus types 1–3 titres ≥ 8 (1/dilution). Following vaccination with DTaP-IPV, anti-diphtheria
and anti-tetanus antibody concentrations ≥0.1 IU/mL and anti-poliovirus types 1–3 antibody titres ≥8
(1/dilution) were achieved in all participants. DTaP-IPV was well tolerated in this study. There were no
serious adverse events during the study, and no participant withdrew because of adverse events.
Discussion: The present study confirmed the long-term immunity conferred by Td-IPV when given as a
booster dose, and supports the use of Td-IPV as a second booster at 6 years of age in children previously
vaccinated against diphtheria, tetanus and poliomyelitis types 1–3.
© 2015 Elsevier Ltd. All rights reserved.

Abbreviations: ANSM, Agence Nationale de Sécurité du Médicament et des Produits de Santé (the French national agency for the safety of drugs and health products); aP,
standard dose of acellular pertussis vaccine; ap, low dose of acellular pertussis vaccine; BS, blood sample; CI, confidence interval; DTaP-IPV, diphtheria, tetanus, aP and IPV
types 1–3 vaccine; DT-IPV, combined booster of standard-dose diphtheria, tetanus and IPV types 1–3 vaccine; ELISA, enzyme-linked immunosorbent assay; EU, European
Union; GMC, geometric mean concentration; GMCR, geometric mean of individual post-/pre-booster antibody concentrations ratio; GMT, geometric mean titre; GMTR,
geometric mean of individual post-/pre-booster antibody titres ratio; IPV, inactivated poliovirus vaccine; SPC, Summary of Product Characteristics; SN, seroneutralization;
Td-IPV, combined booster of low-dose diphtheria, tetanus and IPV types 1–3 vaccine; WHO, World Health Organization.
∗ Corresponding author. Tel.: +33 4 37 28 4579.
E-mail addresses: vincent.gajdos@abc.aphp.fr (V. Gajdos), emmanuel.vidor@sanofipasteur.com (E. Vidor), pr.richard@laposte.net (P. Richard), ctran@spmsd.com (C. Tran),
csadorge@spmsd.com (C. Sadorge).

http://dx.doi.org/10.1016/j.vaccine.2015.06.036
0264-410X/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Gajdos V, et al. Diphtheria, tetanus and poliovirus antibody persistence 5 years after vaccination of
pre-schoolers with two different diphtheria, tetanus and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and immune responses
to a booster dose of DTaP-IPV. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.06.036
G Model
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2 V. Gajdos et al. / Vaccine xxx (2015) xxx–xxx
1. Introduction
Childhood vaccination against diseases such as diphtheria,
tetanus or poliomyelitis has significantly reduced the incidence of
these diseases in industrialized countries [1]. However, following
infant primary series immunizations, antibody titres decrease over
time, and pre-schoolers, adolescents and adults therefore require
booster doses to maintain immunity [2–4]. The importance of
maintaining high antibody levels in these age groups is justified by
the resurgence of diphtheria in the territories of the former Soviet
Union during the early 1990s, and the subsequent control of this
outbreak by mass immunization campaigns [5]. In addition, per-
tussis represents a noticeable health burden, particularly among
adults and adolescents (in whom waning immunity may play a
role) and who may be a source of pertussis transmission to those
not protected by vaccination [5]. Consequently, the maintenance
of immunity among adolescents and adults therefore remains an
important public health goal [6]. Indeed, the World Health Orga-
nization (WHO) has concluded that teenagers and adults who
have not received booster vaccinations are at high risk of disease
[5].
During the first 6 months of life, infants undergo primary immu-
nization, followed by an initial booster at the end of their first year
or during their second year of life. In Europe, most children receive
further booster vaccinations for diphtheria and tetanus, pertussis
and/or poliomyelitis before starting school and again during their
second decade (adolescence) [7,8].
Typically, these booster vaccines contain standard (≥30 IU) or
low (≥2 IU) doses of diphtheria toxoid and different doses of tetanus
toxoid (≥20 IU or ≥40 IU). For pertussis, in most countries in the
European Union (EU), a standard dose of acellular pertussis vaccine
(aP) is given as a booster in pre-school children, and either the same
standard dose or a lower dose (ap) is given as a booster during
adolescence. For poliomyelitis, in nearly all EU countries, vaccines
consist of inactivated poliovirus (IPV) of types 1–3, and the same
formulation is used for primary vaccination of pre-school children
and boosters in adolescents.
Prior to 2013, the recommendation in France was that children
should receive a three-dose primary series at 2, 3 and 4 months
of age of a combined vaccine containing standard-dose diphtheria,
tetanus, aP and IPV types 1–3, followed by a first booster dose at
16–18 months. A second booster with a standard dose of diphtheria,
tetanus and IPV types 1–3 vaccine (DT-IPV) was recommended at 6
years of age, followed by a third booster at 11–13 years of age with
a standard dose of diphtheria, tetanus, aP and IPV types 1–3 vac-
cine [9]. However, due to recurrent shortages of the DT-IPV vaccine
available in France (DT Polio® , Sanofi Pasteur MSD), since 2004 the
use of the low-dose diphtheria, tetanus and IPV types 1–3 vaccine
(Td-IPV; Revaxis® , Sanofi Pasteur MSD) as a booster for children
from 6 years of age has been authorized by the Agence Nationale
de Sécurité du Médicament et des Produits de Santé (ANSM; the
national agency for the safety of drugs and health products).
To support this indication on a permanent basis, the ANSM
required comparative short-term and long-term immunogenicity
data following administration of Td-IPV or DT-IPV as a second
booster in children aged 6 years. To meet this requirement, a ran-
domized, open-label, parallel-group, Phase IIIb trial (F05-TdI-301
study, EudraCT 2005-001446-16; ClinicalTrial.gov NCT00447525)
was performed to compare the immunogenicity and safety of Td-
IPV and DT-IPV vaccines when given as a booster in 6-year-old
children [10].
This study in 2007–2008 included 760 healthy children who
had previously been vaccinated with a three-dose primary series
within their first 6 months of life, followed, at 16–18 months, by
a first booster according to the French vaccination recommenda-
tions. One-month post-vaccination seroprotection rates against the
Please cite this article in press as: Gajdos V, et al. Diphtheria, tetanus and poliovirus antibody persistence 5 years after vaccination of
pre-schoolers with two different diphtheria, tetanus and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and immune responses
to a booster dose of DTaP-IPV. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.06.036
vaccine antigens were similar in the Td-IPV and DT-IPV groups.
However, the geometric mean titres (GMTs) for diphtheria and
tetanus antibodies were higher following DT-IPV vaccine than
after Td-IPV vaccine, reflecting the higher doses of diphtheria
and tetanus toxoids in DT-IPV (≥30 IU and ≥40 IU, respec-
tively), compared with Td-IPV (≥2 IU and ≥20 IU, respectively)
[10].
The present RVX01C study (2012) was a follow-up of chil-
dren enrolled in the previous F05-TdI-301 open-label trial [10].
The RVX01C study was designed to assess the long-term per-
sistence of vaccine-induced antibodies up to the third booster
vaccination recommended at 11–13 years of age, and the immune
response (to diphtheria, tetanus and poliovirus antigens) follow-
ing a diphtheria, tetanus, aP and IPV types 1–3 vaccine (DTaP-IPV;
Tetravac-Acellulaire® , Sanofi Pasteur MSD).
2. Material and methods
The RVX01C study was an open-label, parallel-group (two arms),
multicentre trial performed at 44 study sites (private paediatric
practices or general practices) in France. It was conducted according
to the principles of the Declaration of Helsinki, the International
Conference on Harmonisation, Good Clinical Practice guidelines,
and appropriate French national guidelines and legislation. Written
informed consent was obtained from the parents or legal guardians
of the participating children, and assent was obtained from each
child. The trial was registered with EudraCT (2011-004458-25) and
ClinicalTrial.gov (NCT01546909).
2.1. Study population
Children aged 11–13 years, of either sex, who had received Td-
IPV and DT-IPV vaccines as part of the previous F05-TdI-301 open-
label trial [10] but had no further vaccination against diphtheria,
tetanus, pertussis or poliomyelitis, were eligible for inclusion in
the study. The main exclusion criteria were:
• previous clinical or bacteriological diagnosis of diphtheria,
tetanus, pertussis or poliomyelitis;
• immune impairment;
• cancer chemotherapy within the previous 6 months;
• treatment with serum immunoglobulins or other blood-derived
products within the previous 5 months;
• immunomodulator therapy within the previous 6 weeks;
• receipt of any live or inactivated vaccines 28 or 14 days prior to
vaccination, respectively;
• treatment with daily or alternate-day systemic steroids
(≥20 mg/day prednisone or equivalent) for more than 14
days during the previous 4 weeks;
• hypersensitivity to any component of DTaP-IPV;
• medical conditions than could have interfered with study proce-
dures; and
• severe febrile illness or body temperature >38.0 ◦ C within the 72 h
before vaccination.
2.2. Study vaccination
All participants received a single intramuscular dose (0.5 mL)
on Day 0. The vaccine was given preferably into the deltoid region:
injection into the gluteal region was not permitted.
2.3. Product description
The investigational DTaP-IPV vaccine (batch G7189-2, expiry
date 31 August 2013; batch H7053-2, expiry date 28 February
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2014) was manufactured by Sanofi Pasteur and supplied in pre- Injection site reactions and solicited systemic events were con-
filled 0.5 mL syringes with 16 mm or 25 mm needle sizes. Each sidered to be related to the study vaccine, whereas unsolicited
0.5 mL dose was preservative-free and contained: ≥20 IU diphthe- systemic adverse events were classified as potentially related (pos-
ria toxoid; ≥40 IU tetanus toxoid; 25 ␮g pertussis toxoid; 25 ␮g sible, probable, definite or missing data) or unrelated, based on the
filamentous haemagglutinin; 40, 8 and 32 D-antigen units of IPV investigator’s evaluation. Serious adverse events were defined as
types 1–3, respectively; and 0.3 mg aluminium hydroxide. events resulting in death, that were life-threatening, required inpa-
tient hospitalization or prolongation of existing hospitalization,
2.4. Assessments led to a congenital anomaly/birth defect, resulted in a persistent
or significant disability/incapacity, or were considered a medically
2.4.1. Immunogenicity important event.
Blood samples (5 mL) were obtained within 7 days prior to vac-
cination with DTaP-IPV, and on a single occasion between Day
2.5. Statistical methods
28 and Day 35 after vaccination. Serum was separated by cen-
trifugation within 24 h after collection, and aliquots were frozen
For the primary study endpoints, analyses of antibody persis-
and stored at −20 ◦ C or lower. Antibody levels were measured at
tence were performed on the antibody persistence full analysis
the Sanofi Pasteur Global Immunology Laboratory (Swiftwater, PA,
set, which included all participants who received the study vaccine
USA) with assays previously described [11]. Anti-diphtheria anti-
and had a pre-vaccination immunogenicity evaluation; analyses of
bodies were measured by a seroneutralization (SN) assay on Vero
post-booster immune responses were performed on the per proto-
cells, and by an enzyme-linked immunosorbent assay (ELISA) (data
col set, which excluded participants with protocol violations that
not shown). Anti-tetanus antibodies were measured by ELISA, and
could have interfered with immunogenicity evaluations.
anti-poliovirus antibodies were measured by a neutralization assay
For secondary endpoints, analyses of antibody persistence were
on Vero cells and using wild-type poliovirus. Antibodies to pertussis
performed as described above, whereas analyses of post-booster
toxoid and filamentous haemagglutinin were not measured.
immune responses were performed on the per protocol set and
The primary study endpoints were based on antibody persis-
the post-booster full analysis set, which included all partici-
tence and post-booster immune responses. Antibody persistence
pants who received the study vaccine and had a post-booster
was defined as the proportions of participants with anti-diphtheria
immunogenicity evaluation. Descriptive statistics were used for all
antibody concentrations ≥0.01 IU/mL, anti-tetanus antibody con-
analyses.
centrations ≥0.01 IU/mL, and anti-poliovirus types 1–3 antibody
For primary study endpoints (both antibody persistence and
titres ≥8 (1/dilution). Post-booster immune responses were
post-booster immune response), the proportion of participants
defined as the proportion of participants with anti-diphtheria
with immunogenicity results above the defined thresholds was cal-
antibody concentrations ≥0.1 IU/mL, anti-tetanus antibody con-
culated, together with their two-sided 95% confidence intervals
centrations ≥0.1 IU/mL, and anti-poliovirus types 1–3 antibody
(CIs). The distributions of anti-diphtheria and anti-tetanus anti-
titres ≥8 (1/dilution).
body concentrations, and anti-poliovirus types 1–3 antibody titres
The secondary endpoints for antibody persistence were: the
were plotted as reverse cumulative distribution curves. Descriptive
proportion of participants with anti-diphtheria antibody concen-
safety analyses were performed by group and on the pooled data
trations ≥0.1 IU/mL; anti-diphtheria antibody geometric mean
of the two groups.
concentrations (GMC); the proportion of participants with anti-
All analyses were performed using SAS version 9.2 software
tetanus antibody concentrations ≥0.1 IU/mL; anti-tetanus antibody
(SAS Inc, Cary, NC, USA), and P values below 0.05 were considered
GMC, measured by ELISA; and anti-poliovirus types 1–3 GMTs.
significant.
The secondary endpoints for the post-booster immune response
The sample size determination was based on the assumption
were: the proportion of participants with anti-diphtheria antibody
that the participation rate would be between 30% and 50% of the
concentrations ≥1.0 IU/mL; anti-diphtheria antibody GMC; the
eligible population (participants in the previous study who had
anti-diphtheria geometric mean of individual post-/pre-booster
reached the age of 11 years at the time of the recruitment period).
antibody concentrations ratio (GMCR); the proportion of par-
At the time of protocol development, it was estimated that there
ticipants with anti-tetanus antibody concentrations ≥1.0 IU/mL;
were 532 potentially eligible children, of whom between 160 and
anti-tetanus antibody GMC; the anti-tetanus GMCR; GMTs of anti-
266 (80–133 per vaccine group) would be expected to enrol in the
poliovirus types 1–3 antibodies; and the anti-poliovirus geometric
study. It was concluded that a sample size of 120 participants in
mean of individual post-/pre-booster antibody titres ratio (GMTR).
each vaccine group would result in 95% CIs of 77.3–90.9 for an 85%
expected response rate, and 89.4–98.1 for a 95% expected response
2.4.2. Safety
rate.
Safety was monitored by physical examinations performed on
the day of vaccination, and on Visit 2 (28–35 days after vaccination),
and by the reporting of adverse events, which occurred throughout 3. Results
the study. Serious adverse events were recorded from the time of
consent until Visit 2. Solicited injection site reactions (erythema, Of the 758 children included over 63 investigational sites in the
swelling, pain) and solicited systemic reactions (pyrexia, headache, previous study, 440 children from 44 participating active centres
malaise, myalgia) were recorded over Days 0–7, and unsolicited were eligible to be enrolled in this study. Of these, 163 were not
injection site reactions and systemic reactions were recorded over screened, primarily due to loss to follow-up (n = 88) or refusal to
Days 0–28. participate (n = 39). Overall, 274 of the remaining 277 children were
The solicited reactions were defined in diary cards issued to included in the 2012 follow-up study (Fig. 1), of whom 129 had
the participants as redness for erythema, temperature for pyrexia, previously been vaccinated with Td-IPV, and 145 had previously
feeling unwell for malaise, and muscle aches and pains for myal- received DT-IPV. Of these, 128 (99.2%) and 142 (97.9%), respec-
gia. Erythema and swelling injection site reactions were considered tively, completed the study (Fig. 1). Of the four subjects who did
severe if they covered an area ≥5 cm in diameter; non-measurable not complete the study, three withdrew consent (one in the Td-IPV
injection site reactions and systemic adverse events were consid- group, two in the DT-IPV group), and one participant in the DT-IPV
ered severe if they prevented daily activity or were incapacitating. group was lost to follow-up.

Please cite this article in press as: Gajdos V, et al. Diphtheria, tetanus and poliovirus antibody persistence 5 years after vaccination of
pre-schoolers with two different diphtheria, tetanus and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and immune responses
to a booster dose of DTaP-IPV. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.06.036
G Model
JVAC-16576; No. of Pages 9 ARTICLE IN PRESS
4 V. Gajdos et al. / Vaccine xxx (2015) xxx–xxx

Fig. 1. Disposition of participants.

Demographic characteristics of the participants are summarized
in Table 1. Overall, the mean age of the children was 11.3 years,
with 138 (50.4%) being female; there were no relevant differences
with respect to demographic characteristics of participants who
received Td-IPV and those who received DT-IPV.
3.1. Long-term antibody persistence following Td-IPV and DT-IPV
vaccines
The mean interval between the previous vaccination at 6 years
of age and the collection of the first blood sample in this study was
4.9 years (range 4.4–5.3 years) in the Td-IPV group, and 4.9 years
(range 4.3–5.3 years) in the DT-IPV group. Antibody levels prior to
vaccination with DTaP-IPV measured in the antibody persistence
full analysis set (n = 272) are summarized in Table 2. Overall, at least
96.5% of participants in both groups met the primary outcome crite-
ria (anti-diphtheria and anti-tetanus concentration ≥0.01 IU/mL
and anti-poliovirus types 1–3 titres ≥8 [1/dilution]).
The anti-diphtheria GMC was lower in the Td-IPV group than
in the DT-IPV group, with non-overlapping CIs (Td-IPV: 0.24 IU/mL
[95% CI 0.18, 0.33]; DT-IPV: 0.62 IU/mL [95% CI 0.48, 0.81]). The
reverse cumulative distribution curves for anti-diphtheria, anti-
tetanus and anti-poliovirus types 1–3 antibody levels are shown
in Fig. 2.

Please cite this article in press as: Gajdos V, et al. Diphtheria, tetanus and poliovirus antibody persistence 5 years after vaccination of
pre-schoolers with two different diphtheria, tetanus and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and immune responses
to a booster dose of DTaP-IPV. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.06.036
G Model
JVAC-16576; No. of Pages 9 ARTICLE IN PRESS
V. Gajdos et al. / Vaccine xxx (2015) xxx–xxx 5

Table 1 The incidences of solicited injection site reactions and of

Participants’ demographic characteristics.
solicited systemic vaccine-related adverse events for the over-
Td-IPV (n = 129) DT-IPV (n = 145) All (n = 274) all population are presented in Table 4. Solicited injection site
Age (years)a 11.4 (0.3) 11.3 (0.3) 11.3 (0.3) reactions occurred between Day 0 and Day 7 in 238 participants
Female/male ratio (87.5%). The most commonly reported reaction was injection site
Number 61/68 77/68 138/136 pain (86.4%). Injection site erythema and swelling were reported
Percentage 47.3/52.7 53.1/46.9 50.4/49.6 by 46.7% and 41.2% of participants, respectively. The incidence of
Weight (kg)a 40.2 (8.8) 41.4 (10.1) 40.9 (9.5)
severe injection site reactions was 10.7% for erythema, 13.6% for
Height (cm)a 147.3 (7.1) 148.3 (7.7) 147.8 (7.4)
pain, and 12.1% for swelling. Unsolicited injection site reactions
a
Mean (standard deviation).
were reported between Day 0 and Day 28 by eight participants
(2.9%). The most common of these was pruritus, which occurred
in four participants (1.5%); injection site haematoma, pain and
Table 2 warmth, and joint ankylosis were each reported by one participant
Serological status prior to vaccination with DTaP-IPV against diphtheria, tetanus and (0.4%).
poliovirus types 1–3 according to the booster vaccine received at 6 years of agea .
Solicited vaccine-related systemic adverse events occurred
Td-IPV (n = 128) DT-IPV (n = 144) between Day 0 and Day 7 in 113 participants (41.5%). The most
Anti-diphtheria (SN) common of these was myalgia (31.6%). Headache was reported in
n ≥ 0.01 IU/mL 126 143 21.7%, and malaise and pyrexia were reported by 6.3% and 4.4%,
% (95% CI) 98.4 (94.5, 99.8) 99.3 (96.2, 100.0) respectively.
n ≥ 0.1 IU/mL 81 124
Unsolicited vaccine-related systemic adverse events occurred
% (95% CI) 63.3 (54.3, 71.6) 86.1 (79.4, 91.3)
GMC (95% CI), IU/mL 0.24 (0.18, 0.33) 0.62 (0.48, 0.81)
between Day 0 and Day 28 in 11 participants (4.0%). The most
Anti-tetanus (ELISA) common of these was headache, which was reported in three par-
n ≥ 0.01 IU/mL 128 143 ticipants (1.1%).
% (95% CI) 100.0 (97.2, 100.0) 100.0 (97.5, 100.0) Most systemic adverse effects occurring during Days 0–7 were
n ≥ 0.1 IU/mL 123 135
mild or moderate in intensity. Severe systemic adverse events
% (95% CI) 96.1 (91.1, 98.7) 94.4 (89.3, 97.6)
GMC (95% CI), IU/mL 0.73 (0.61, 0.88) 0.91 (0.76, 1.09) occurred in nine participants (3.3%) for myalgia, in six (2.2%) for
Anti-poliovirus type 1 (SN) headache, in two (0.7%) for malaise, and in one (0.4%) for pyrexia.
n ≥ 8 (1/dilution) 126 144 No severe systemic adverse event occurred in more than 1% of
% (95% CI) 98.4 (94.5, 99.8) 100.0 (97.5, 100)
participants after Day 7. The frequencies of adverse events were
GMT (95% CI), (1/dilution) 233 (186, 291) 259 (216, 311)
Anti-poliovirus type 2 (SN)
comparable between groups (data not shown).
n ≥ 8 (1/dilution) 128 144
% (95% CI) 100.0 (97.2, 100.0) 100.0 (97.5, 100.0)
GMT (95% CI), (1/dilution) 405 (338, 484) 276 (231, 331) 4. Discussion
Anti-poliovirus type 3 (SN)
n ≥ 8 (1/dilution) 127 139
% (95% CI) 99.2 (95.7, 100.0) 96.5 (92.1, 98.9) The present study confirmed the long-term immunity conferred
GMT (95% CI), (1/dilution) 314 (255, 388) 134 (108, 166) by Td-IPV, which contains reduced-dose diphtheria, tetanus and
Abbreviations: CI; confidence interval; ELISA; enzyme-linked immunosorbent
poliovirus types 1–3, when given as a booster dose at 6 years of
assay; GMC; geometric mean concentration; GMT; geometric mean titre; SN; age. The observed proportions of participants with a residual anti-
seroneutralization. body level ≥0.01 IU/mL against diphtheria and tetanus, and ≥8
a
Antibody persistence full analysis set, n = 272. (1/dilution) against poliovirus types 1–3 were comparable between
children who had previously been vaccinated with Td-IPV and
those who had received DT-IPV at 6 years of age.
Following vaccination with DTaP-IPV, which contains standard-
3.2. Booster response to DTaP-IPV vaccine
dose diphtheria, tetanus, aP and poliovirus types 1–3, all children
attained anti-diphtheria and anti-tetanus antibody concentrations
Following vaccination with DTaP-IPV, anti-diphtheria and anti-
≥0.1 IU/mL and anti-poliovirus types 1–3 antibody titres ≥8 (1/dilu-
tetanus antibody concentrations ≥0.1 IU/mL, and anti-poliovirus
tion).
types 1–3 antibody titres ≥8 (1/dilution) were achieved in all par-
The seroprotective cut-offs used in this study were based
ticipants (Table 3). The anti-diphtheria antibody GMCR was higher
on well-accepted thresholds [12–15]. The cut-off for diphtheria
in the Td-IPV group than in the DT-IPV group (32.2 versus 11.6,
was set at ≥0.1 IU/mL, as it is accepted that this antibody level
respectively), leading both the GMC and the proportion of sub-
(measured by SN) is required for full protection, while a titre
jects with post-booster antibody concentrations ≥1.0 IU/mL to be
of 0.01 IU/mL provides basic clinical immunity [13,15]. For anti-
comparable in the two groups. Post-booster anti-tetanus antibody
tetanus antibodies, a cut-off of ≥0.1 IU/mL was chosen based on the
GMCs, GMCRs, the proportion of participants with post-booster
previously defined level of 0.1–0.2 IU/mL by ELISA [14]. The cut-off
concentrations ≥1.0 IU/mL and post-booster GMTs (1/dilution), and
value for anti-poliovirus antibodies was set ≥8 (1/dilution), as this
GMTRs for anti-poliovirus types 1–3 were comparable between the
is the accepted antibody level (measured by SN) for evaluation of
two groups. The reverse cumulative distribution curves for anti-
seroprotection in clinical trials with these vaccines [12,15].
diphtheria, anti-tetanus, anti-poliovirus types 1–3 antibodies are
In the original Phase IIIb study [10], booster vaccination with
shown in Fig. 2.
Td-IPV and DT-IPV at 6 years of age resulted in similar (non-
inferior) seroprotection rates for the five antigens. One month
3.3. Safety after vaccination, 100% of children in the per protocol set reached
the pre-determined antibody level of 8 (1/dilution) for the three
DTaP-IPV was well tolerated in this study. Overall, 88.2% of par- poliovirus serotypes. In the Td-IPV and DT-IPV groups, the anti-
ticipants reported at least one adverse event within 28 days after body titre threshold of 0.1 IU/mL was reached by 98.6% and 99.3%
vaccination. There were no serious adverse events during the study, of children for diphtheria, respectively, and by 99.6% and 100% of
and no participant withdrew because of adverse events. children for tetanus, respectively.

Please cite this article in press as: Gajdos V, et al. Diphtheria, tetanus and poliovirus antibody persistence 5 years after vaccination of
pre-schoolers with two different diphtheria, tetanus and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and immune responses
to a booster dose of DTaP-IPV. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.06.036
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Fig. 2. Reverse cumulative distribution curves for diphtheria, tetanus, and polio types 1–3 antibody titres 5 years after vaccination with Td-IPV or DT-IPV vaccines, and 1-
month post-vaccination with DTaP-IPV. (A) Anti-diphtheria antibody concentration (SN). (B) Anti-tetanus antibody concentration (ELISA). (C) Anti-poliovirus type 1 antibody
titre (SN). (D) Anti-poliovirus type 2 antibody titre (SN). (E) Anti-poliovirus type 3 antibody titre (SN).

Please cite this article in press as: Gajdos V, et al. Diphtheria, tetanus and poliovirus antibody persistence 5 years after vaccination of
pre-schoolers with two different diphtheria, tetanus and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and immune responses
to a booster dose of DTaP-IPV. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.06.036
G Model
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Table 3 Table 4
Serological status 1 month following vaccination with DTaP-IPV against diphtheria, Adverse events reported during the study.
tetanus and poliomyelitis types 1–3 according to the booster vaccine received at 6
years of age.a Participants,
number (%)
Td-IPV (n = 124) DT-IPV (n = 131)
Any adverse event, days 0–28 240 (88.2)
Anti-diphtheria (SN) Solicited injection site reactions, days 0–7 238 (87.5)
n ≥ 0.1 IU/mL 124 131 Erythema 127 (46.7)
% (95% CI) 100.0 (97.1, 100.0) 100.0 (97.2, 100.0) ≥5.0 cm 29 (10.7)
n ≥ 1.0 IU/mL 122 127 Pain 235 (86.4)
% (95% CI) 98.4 (94.3, 99.8) 96.9 (92.4, 99.2) Severea 37 (13.6)
GMC (95% CI), IU/mL 7.36 (6.08, 8.92) 7.57 (6.25, 9.17) Swelling 112 (41.2)
GMCR (95% CI), IU/mL 32.2 (24.2, 42.8) 11.6 (9.1, 14.6) ≥5.0 cm 33 (12.1)
Anti-tetanus (ELISA) Unsolicited injection site reactions, days 0–28 8 (2.9)
n ≥ 0.1 IU/mL 124 131 Severe or ≥5 cm 3 (1.1)
% (95% CI) 100.0 (97.1, 100.0) 100.0 (97.2, 100.0) Systemic adverse events, days 0–28 131 (48.2)
n ≥ 1.0 IU/mL 124 130 Solicited vaccine-related systemic adverse events, days 0–7 113 (41.5)
% (95% CI) 100.0 (97.1, 100.0) 99.2 (95.8, 100.0) Headache 59 (21.7)
GMC (95% CI), IU/mL 8.08 (7.16, 9.11) 7.83 (6.96, 8.80) Severea 6 (2.2)
GMCR (95% CI), IU/mL 11.5 (9.3, 14.3) 8.2 (6.8, 10.0) Malaise 17 (6.3)
Anti-poliovirus type 1 (SN) Severe 2 (0.7)
n ≥ 8 (1/dilution) 124 131 Myalgia 86 (31.6)
% (95% CI) 100.0 (97.1, 100.0) 100.0 (97.2, 100.0) Severe 9 (3.3)
GMT (95% CI), (1/dilution) 1557 (1245, 1948) 1483 (1236, 1779) Pyrexia 12 (4.4)
GMTR (95% CI), (1/dilution) 6.9 (5.2, 9.2) 5.9 (4.5, 7.7) >39.5 ◦ C 1 (0.4)
Anti-poliovirus type 2 (SN) Unsolicited vaccine-related systemic adverse events, days 0–28 11 (4.0)
n ≥ 8 (1/dilution) 124 131 Severe or >39.5 ◦ C 1 (0.4)
% (95% CI) 100.0 (97.1, 100.0) 100.0 (97.2, 100.0) a
Severe: prevents daily activity/incapacitating with inability to work or do usual
GMT (95% CI), (1/dilution) 2491 (2028, 3058) 2432 (2051, 2884)
activity.
GMTR (95% CI), (1/dilution) 6.4 (4.9, 8.3) 8.7 (6.8, 11.1)
Anti-poliovirus type 3 (SN)
n ≥ 8 (1/dilution) 124 131
% (95% CI) 100.0 (97.1, 100.0) 100.0 (97.2, 100.0)
GMT (95% CI), (1/dilution) 1948 (1607, 2360) 2356 (1924, 2885) and a third booster with a Tdap-IPV vaccine (low-dose diphthe-
GMTR (95% CI), (1/dilution) 6.5 (5.1, 8.4) 17.2 (13.1, 22.7) ria, tetanus, low-dose acellular pertussis, inactivated poliovirus
Abbreviations: CI; confidence interval; ELISA; enzyme-linked immunosorbent types 1–3) at 11–13 years of age [9]. This means that, for immu-
assay; GMC; geometric mean concentration; GMCR; geometric mean of individ- nization against diphtheria, tetanus and poliovirus, the previous
ual post-/pre-booster antibody concentrations ratio; GMT; geometric mean titre; three-dose primary series has been replaced by a two-dose pri-
GMTR; geometric mean of individual titres ratio post-/pre-booster; SN; seroneu-
tralization.
mary series still followed by booster doses within the second year
a
Per protocol set (n = 255). of life, at pre-school and during adolescence. For pertussis vacci-
nation, the previous three-dose primary series followed by booster
doses within the second year of life and during adolescence has
been replaced by a two-dose primary series followed by booster
The GMTs for diphtheria and tetanus were higher after a doses within the second year of life, at pre-school and during
booster dose with DT-IPV (23.3 IU/mL [19.5; 27.9] and 13.9 IU/mL adolescence. In the light of these new recommendations, even if
[12.2; 15.8], respectively) than after Td-IPV (3.7 IU/mL [3.1; 4.4] the mean diphtheria residual antibody level was lower in sub-
and 9.4 IU/mL [8.3; 10.6], respectively). This reflected the higher jects who received the low diphtheria toxoid containing vaccine
contents of diphtheria and tetanus toxoids in DT-IPV (≥30 IU and compared with those who received the regular content diphthe-
≥40 IU, respectively) than in Td-IPV (≥2 IU and ≥20 IU, respectively) ria toxoid containing vaccine, the present findings are reassuring
[10]. in that a comparable proportion of subjects with an antibody level
In the present study, 5 years after vaccination with Td-IPV and ≥0.01 IU/mL at 11–13 years of age (at the time of booster vaccina-
DT-IPV, and prior to the booster vaccination with DTaP-IPV, based tion) was observed.
on non-overlapping CIs, the anti-diphtheria GMC was still lower DTaP-IPV was well tolerated in this study, and no major safety
in children previously vaccinated with Td-IPV than in those who issues were identified. The incidences of solicited injection site
had previously received DT-IPV (0.24 IU/mL [0.18; 0.33] versus reactions (erythema, pain, swelling) and solicited systemic adverse
0.62 IU/mL [0.48; 0.81], respectively). By contrast, no such dif- events (headache, myalgia) were consistent with the data reported
ference in anti-tetanus GMC persisted 5 years after vaccination in the European Summary of Product Characteristics (SPC) [17].
with Td-IPV and DT-IPV. After vaccination with DTaP-IPV, the anti- Although severe injection site erythema or injection site
diphtheria and anti-tetanus GMCs were comparable irrespective swelling were reported with a higher frequency (more than 10% of
of the previous vaccination. Not all differences persisted after the study participants) than that reported in the SPC (<10%), it should
booster vaccination for all antigens (Fig. 2). be noted that the Sanofi Pasteur scale used was that for young
The immune response to the aP component of DTaP-IPV was children (aged 2–11 years). This has a more stringent definition
not evaluated in this study, which was a follow up of the study of severity in size (≥5 cm) than the Sanofi Pasteur scale used for
by Gajdos and colleagues [10] in which subjects did not receive children aged 11–13 years, in which severe erythema or swelling
pertussis-containing vaccine. However, a previous study, in which is defined as affecting an area ≥10 cm in diameter (data on file). It
children aged 8–12 years received either DTaP-IPV or DT-IPV as a should also be noted that no safety signal relating to injection site
booster vaccination, showed good immune responses to all anti- reactions has been reported during extensive clinical experience
gens, including pertussis [16]. with DTaP-IPV in the 95 countries (including France) where this
In 2013, the vaccination recommendations in France changed: product is licensed. Injection site pruritus was reported by 1.5% of
children are now recommended to receive a two-dose primary vac- participants in the present study. This is consistent with the report
cination at 2 and 4 months of age, followed by a first booster at of allergy-like symptoms such as rash, erythema and urticaria in
11 months, a second booster with a DTaP-IPV vaccine at 6 years, the SPC [17].

Please cite this article in press as: Gajdos V, et al. Diphtheria, tetanus and poliovirus antibody persistence 5 years after vaccination of
pre-schoolers with two different diphtheria, tetanus and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and immune responses
to a booster dose of DTaP-IPV. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.06.036
G Model
JVAC-16576; No. of Pages 9 ARTICLE IN PRESS
8 V. Gajdos et al. / Vaccine xxx (2015) xxx–xxx
In contrast to injection site reactions, the incidence of fever
in this study was lower than that reported in the SPC, where it
is described as ‘very common’ (≥10%). However, the SPC data are
derived from studies in younger children (aged 5–6 years) [18,19],
in whom fever is more common than in older children. Similarly,
malaise is described as very common in the SPC, but occurred in
only 6% of participants in this study. Together, these safety find-
ings are consistent with the study by Auzerie and colleagues [16],
in which booster vaccination with DTaP-IPV did not increase the
incidence of injection site or systemic reactions compared with
DT-IPV.
5. Conclusions
The study results show that, in children aged 11–13 years
who had previously been vaccinated at 6 years of age with Td-
IPV or DT-IPV, the residual mean antibody level was lower with
the low-dose diphtheria vaccine. However at the time of the
adolescent booster the observed proportion of subjects with an
antibody level ≥0.01 IU/mL against diphtheria and tetanus, and
≥8 (1/dilution) against poliomyelitis types 1–3 were comparable.
Furthermore, 1 month after vaccination with DTaP-IPV, all the par-
ticipants attained an antibody level ≥0.1 IU/mL against diphtheria
and tetanus, and ≥8 (1/dilution) against poliomyelitis types 1–3.
Thus, the immunogenicity results of this study support the use
of Td-IPV as a second booster at 6 years of age in children pre-
viously vaccinated against diphtheria, tetanus and poliomyelitis
types 1–3.
The role of the funding source
This research was sponsored by Sanofi Pasteur MSD.
Conflict of interest statement
VG activities were supported by Association Pédiatrique des
Groupes d’Accueil et de Recherche (APGAR), which received finan-
cial support from Sanofi Pasteur MSD for travel associated with the
conduct of the study and for participation in data and manuscript
review activities; EV is an employee of Sanofi Pasteur; PR, CT and
CS are employees of Sanofi Pasteur MSD.
Acknowledgements
The authors would like to thank the participants in the trial,
as well as the investigators and study-site personnel for their
contribution to the study: Jean-Pierre Arsène, Le Havre; Oum-
ran Arwani, Illkirch-Graffenstaden; Philippe Beignot-Devalmont,
Rouen; Kamel Belaid, Nogent-sur-Marne; Nassira Belaroussi,
Boulogne-Billancourt; Gérard Beley, Essey-lès-Nancy; Marc Berr,
Frouard; Bertrand Bineau, Louverne; Bénédicte Blanc, Maromme;
Etienne Blot, Rouen; Fabrice Bouillot, Essey-lès-Nancy; Sophie
Boulanger el Abbadi, Caen; René Bressollette, Angers; Jean-Louis
Brochot, Besançon; Georges Delamare, Blois; Dominique Del-
sart, Bersée; Serge Faligot, Cholet; Rémi Gatard, Poitiers; Philippe
Gautret, Marseille; Philippe Hacquard, Pont-à-Mousson; Christian
Hulin, Arras; Yoko Kikuchi-Maurice, Montpellier; Xavier Lanse, Le
Havre; Bernard Lauer, Colombey-les-Belles; Charles Leissler, Blois;
François Levavasseur, Rouen; Jean-Claude Leveque, Châlons-en-
Champagne; Benoît Logre, Floirac; Jean-Louis Navarre, Manduel;
Jean-Claude Oilleau, Dax; Jacques Orbegozo, Besançon; Chris-
tian Petit, Draguignan; Alain Picard, Chigny-les-Roses; Eric Pierot,
Colombey-les-Belles; Nicole Roessler-Huck, Ostwald; Elizabeth
Rofe-Sotto, Saint-Ouen; Patrice Savary, Champdeniers; Patrick
Please cite this article in press as: Gajdos V, et al. Diphtheria, tetanus and poliovirus antibody persistence 5 years after vaccination of
pre-schoolers with two different diphtheria, tetanus and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and immune responses
to a booster dose of DTaP-IPV. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.06.036
Schouman, Caen; David Somerville, Brest; Daniel Sror, Lingolsheim;
Franck Thollot, Essey-lès-Nancy; Nicole Walle, Asnières-sur-Seine;
Christian Wolff, Haguenau; Christophe Ythier, Quimper. They also
would like to thank Xavier Cornen, Anne Schuyleman, Maryline
Gonon and Anne-Laure Chabanon (Sanofi Pasteur MSD), Banu
Demirci-Guillermet and Stéphanie Piron (ICTA PM) for their con-
tribution to the conduct of the study; Marie-Cécile Levant (Sanofi
Pasteur MSD) for her critical review of the study results, and Steve
Hildreth (Global Clinical Immunology Platform, Sanofi Pasteur).
The authors take full responsibility for the content of this con-
tribution and thank Communigen, Oxford, UK (supported by Sanofi
Pasteur MSD) for preparing the drafts.
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Please cite this article in press as: Gajdos V, et al. Diphtheria, tetanus and poliovirus antibody persistence 5 years after vaccination of
pre-schoolers with two different diphtheria, tetanus and inactivated poliomyelitis vaccines (Td-IPV or DT-IPV) and immune responses
to a booster dose of DTaP-IPV. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.06.036