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Indian Pediatr 2017;54: 15 -20 |
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Immunogenicity and Safety of a Liquid
Hexavalent Vaccine in Indian Infants
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Jugesh Chhatwal, #Sanjay
Lalwani and *Emmanuel Vidor
From Pediatrics Department, CMC and Hospital, Brown
Road, Ludhiana, Punjab; #Pediatrics Department, Bharati
Vidyapeeth University Medical College, Pune; India; and *Sanofi
Pasteur, Lyon, France.
Correspondence to: Emmanuel Vidor, Sanofi Pasteur, 2
avenue Pont Pasteur, 69367 Lyon, France.
Email: [email protected]
Received: February 16, 2016;
Initial review: March 28, 2016;
Accepted: September 03, 2016.
Published online: November 05, 2016.
PII:S097475591600026
WHO
Universal Trial Number: U1111-1127-6936.
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Objective: To evaluate the immunogenicity and safety of a fully
liquid, hexavalent diphtheria-tetanus-acellular pertussis–inactivated
poliovirus–hepatitis B–Haemophilus influenzae type b (DTaP-IPV-HB-PRP~T)
vaccine in Indian infants.
Design: Phase III, single-arm
study.
Setting: Two tertiary-care
hospitals.
Participants: 177 healthy,
6-week-old infants.
Intervention: All participants
received hepatitis B vaccine and Oral polio vaccine (OPV) at birth and
DTaP-IPV-HB-PRP~T at 6, 10, 14 weeks of age.
Main outcome measures: Serum was
analyzed for immune responses to all antigens 1 month post-3rd dose;
safety was assessed for 30 minutes post-vaccination, and for 7 days
(solicited reactions) and 30 days (unsolicited events).
Results: Seroprotection rates
were 100% for anti-HB ( ³10
mIU/mL), anti-PRP (³0.15
µg/mL), anti-T (³0.01
IU/mL), anti-polio 1, 2, and 3 (³8
[1/dil]), and 99.3% for diphtheria (³0.01
IU/mL). For the pertussis antigens, vaccine response rate was 93.8% for
anti-PT and 99.3% for anti-FHA. 37.9% and 54.6% of participants
experienced at least one solicited injection site and systemic reaction,
respectively, and 20.3% of participants experienced at least one
unsolicited event (none of which was related to the vaccination). Four
serious adverse events (including one death) were reported, but none was
related to the vaccination.
Conclusion: The fully liquid DTaP-IPV-HB-PRP~T
vaccine is highly immunogenic in infants in India when administered in a
6, 10, 14 week schedule along with HB and OPV administered at birth, and
was well tolerated.
Keywords: Diphtheria-Pertussis-Tetanus
vaccine, Haemophilus influenzae, Hepatitis B, Immunization, Poliovirus,
Vaccination program.
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T he improved safety of acellular pertussis (aP)-combination
vaccines compared to whole cell pertussis (wP) vaccines [1], the need to
deploy routine Haemophilus influenzae type b (Hib) and hepatitis
B (HB) vaccination [2,3], and the need for inactivated poliovirus
vaccine (IPV) in the global polio eradication strategy [4] are current
drivers for a wide expansion of the use of hexavalent combination
vaccines. Such vaccines are increasingly pivotal to national
immunization programs [5]. A fully liquid hexavalent DTaP-IPV-HB-PRP~T
vaccine was developed based on a pentavalent vaccine (Pentaxim/Pentavac)
that has a well-documented safety, immunogenicity, and effectiveness
profile, based on extensive clinical experience [6]. This hexavalent
vaccine incorporates a new HB antigen, has proven immunogenicity and
safety [7-10], and was approved by the European Medicines Agency (EMA)
via the Centralized Procedure and licensed in 104 countries as of
August 2016. The 6, 10, 14 weeks-of-age schedule is recommended in many
countries. Many similar combination vaccines have been documented using
this regimen [11-14], which is used in many national immunization
programs (NIPs). The present study was undertaken after the initial
licensure of the DTaP-IPV-HB-PRP~T vaccine to evaluate its performance
in Indian infants, when administered in the 6, 10, 14 week infant
primary series schedule, with HB vaccine and OPV administered at birth
as per the Indian NIP recommendations [15].
Methods
This was a Phase III, open-label, multi-center study
conducted in India. The study was conducted between February 2014 and
October 2014 in two hospitals, (Christian Medical College and Hospital,
Ludhiana, Punjab; and Bharatiya Vidya Peeth Hospital, Pune). Independent
ethics committees of both institutes approved the study protocol.
Informed consent was obtained from the parent(s) or legally acceptable
representative(s) of each participant. Healthy infants aged between
42-56 days (6-8 weeks), born at full term ( ³37
weeks) to HBsAg seronegative mothers, with birth weight
³2.5 kg and who had
received one dose of HB vaccine and OPV at birth per Indian NIP were
eligible for inclusion. The main exclusion criteria were: recent (in the
4 weeks prior to the first vaccination), current, or planned
participation in another clinical study or non-study vaccination (except
rotavirus) during or in the 4 weeks prior to the study; any prior
vaccination against diphtheria, tetanus, pertussis, poliomyelitis,
Haemo-philus influenzae type b (Hib), or any history of these
infections; receipt of blood products or immune suppressants for more
than two consecutive weeks since birth; personal/maternal history of
human immuno-deficiency virus; known hypersensitivity to any vaccine
component; history of seizures or encephalopathy; bleeding disorder;
chronic illness that could interfere with study conduct/completion; or
acute illness at enrolment.
The investigational vaccine, DTaP-IPV-HB-PRP~T (batch
number S4370) was manufactured by Sanofi Pasteur and was presented as a
fully liquid suspension for injection in single dose (0.5 mL) pre-filled
syringes and stored at + 2 to + 8°C. Each pre-filled syringe contained
³20 IU (30
limit of flocculation [Lf]) D-toxoid;
³40 IU (10 Lf) T-toxoid;
25 µg PT; 25 µg FHA; 40, 8 and 32 D antigen units of IPV type 1, 2 and
3, respectively; 10 µg HBsAg; 12 µg Hib polysaccharide conjugated to
22-36 µg tetanus protein (PRP~T); and 0.6 mg aluminum hydroxide.
Enrolled participants received DTaP-IPV-HB-PRP~T at
6, 10 and 14 weeks of age, administered into the right thigh. Blood
samples were taken prior to the first vaccination (Day 0) and 1 month
after the third vaccination (Day 90, approximately 18 weeks of age).
Anti-HB, anti-diphtheria, anti-PT, and anti-FHA anti-bodies were
determined using the Day 0 samples, and all antibodies were determined
using the Day 90 samples. Assays were performed at a centralized
laboratory under the responsibility of the Sponsor’s Global Clinical
Immunology laboratory (Swiftwater, PA, USA). Anti-diphtheria (IU/mL)
antibody concentrations and anti-polio 1, 2, 3 (1/dil) antibody titers
were assayed by neutralization assay, anti-tetanus (IU/mL), anti-PT (EU/mL)
and anti-FHA (EU/mL) concentrations by enzyme linked immunosorbent
assays (ELISA), anti-HBsAg concentrations (mIU/mL) by a commercially
available chemiluminescence assay (VITROS ECi/ECiQ), and anti-PRP-T
concentrations (µg/mL) by radio-immunoassay.
Immediate adverse reactions (ARs) were monitored for
30 minutes after each vaccination (the term AR being used to define an
adverse event [AE] that was considered to be related to the vaccination,
with all immediate AEs being classified as ARs). For 7 days after each
vaccination, parent(s)/legal representative(s) used diary cards to
record the duration and intensity of pre-defined (solicited) injection
site (tenderness, redness, and swelling) and systemic (temperature,
vomiting, crying abnormal, drowsiness, appetite lost, irritability)
reactions (also considered by definition to be related to the
vaccination). For temperature measurement, the preferred route was
axillary, and parent(s)/legal guardian(s) were to record the route used
and the classification for intensity was made at the time of the
statistical analysis. Unsolicited AEs were recorded using diary cards
for 30 days after each vaccination: unsolicited injection site AEs were
automatically considered to be related to the vaccination but for each
unsolicited systemic AE, the investigators assessed the relationship to
the vaccination. Serious adverse events (SAEs) were collected throughout
the study and until 1 month after the last vaccination, and the
investigators assessed their relationship to the vaccination.
Statistical analysis: All analyses were
descriptive. The 95% confidence intervals (CIs) were calculated using
the exact binomial method (Clopper-Pearson method) for single
proportions and using the normal approximation of the log 10
titers, followed by a back transformation for geometric mean
concentrations (GMCs) and geometric mean titers (GMTs). Immunogenicity
criteria were described for all valid serological results from all
available sera obtained before the first dose and 1 month after the
third dose. The antibody thresholds and criteria used to compute
seroprotective (SP) and vaccine response (VR) rates for the various
antigens are presented in Table I and Table II.
Geometric mean concentrations (GMCs) (anti-D, anti-T, anti-PT,
anti-FHA, anti-HB and anti-PRP), geometric mean titers (GMTs)
(anti-polio 1, 2, 3), and GMC and GMT ratios (post-dose 3/pre-dose 1)
were also calculated. Assuming seroprotection/seroconversion rates of
³94% for any
given vaccine antigen, a sample size of 150 evaluable participants
ensured 95% CI limits within a range less than 8.3 percentage points for
all antibody responses. For safety, this sample size allowed, with 95%
probability, the observation of any given AE occurring with a true
frequency of 2% or more, using the rule of three. Assuming an attrition
rate of approximately 15%, 177 participants were to be included in the
study. Data from the per protocol (PP) population (participants with no
protocol violation that could have interfered with the primary
evaluation criteria) are presented for all immunogenicity assessments;
the evaluation of safety was done using the full analysis set (FAS)
(participants who received at least one vaccination). All statistical
analyses were done using SAS software, at least Version 9.2 (SAS
Institute, Cary, NC, USA).
TABLE I Seroprotection Rates and Vaccine Response Rates 1 Month Post-dose 3
Antibody |
Threshold |
% participants |
|
|
(95% CI) #(N=156) |
Anti-HB |
≥10 mIU/mL |
100.0 (97.6; 100) |
Anti-PRP |
≥0.15 µg/mL |
100.0 (97.7; 100) |
Anti-D |
>0.01 IU/mL |
99.3 (95.9; 100) |
Anti-T |
>0.01 IU/mL |
100.0 (97.3; 100) |
Anti-polio type 1 |
≥8 (1/dil) |
100.0 (97.5; 100) |
Anti-polio type 2 |
≥8 (1/dil) |
100.0 (97.5; 100) |
Anti-polio type 3 |
≥8 (1/dil) |
100.0 (97.5; 100) |
Anti-PT |
VR* |
93.8 (88.6; 97.1) |
Anti-FHA |
VR* |
99.3 (96.3; 100) |
#Data are seroprotection rate for anti-HB, anti-PRP,
anti-D, anti-T, anti-polio 1, 2, 3, and vaccine response rate
for anti-PT and anti-FHA; *%participants with
post-dose 3 concentration ≥4 ×LLOQ
of the assay (2 IU/mL) if pre-vaccination concentration was <4 ×
LLOQ or with post-dose 3 concentration ≥pre-vaccination
concentrations if pre-vaccination concentrations
≥4 × LLOQ. |
TABLE II Immunogenicity Results Pre-dose 1 and Post-dose 3 (N=156)
Antibody |
Criteria |
% participants (95% CI)
#(N=156) |
|
|
Day 0 |
Day 90 |
Anti-HB |
≥10 mIU/mL |
13.2 (8.23;19.6) |
100 (97.6;100) |
|
GMC (mIU/mL) |
3.78 (3.23;4.43) |
2491 (2073;2995) |
Anti-PRP |
≥0.15 µg/mL |
ND |
100 (97.7;100) |
|
≥1.0 µg/mL |
ND |
93.6 (88.5;96.9) |
|
GMC (µg/mL) |
ND |
7.86 (6.35; 9.73) |
Anti-D |
≥0.01 IU/mL |
67.1 (59.0;74.5) |
99.3 (95.9;100) |
|
≥0.1 IU/mL |
15.8 (10.4;22.6) |
49.6 (40.9;58.4) |
|
GMC (IU/mL) |
0.019 (0.015;0.025) |
0.120 (0.099;0.146) |
Anti-T |
≥0.01 IU/mL |
ND |
100.0 (97.3;100) |
|
GMC (IU/mL) |
ND |
1.95 (1.75; 2.17) |
Anti-polio type 1 |
≥1:8 (1/dil) |
ND |
100 (97.5;100) |
|
GMT ([1/dil)) |
ND |
1124 (861;1468) |
Anti-polio type 2 |
≥1:8 (1/dil) |
ND |
100 (97.5;100) |
|
GMT ([1/dil)) |
ND |
1401 (1108;1771) |
Anti-polio type 3 |
≥1:8 (1/dil) |
ND |
100 (97.5;100) |
|
GMT ([1/dil)) |
ND |
2019 (1672;2437) |
Anti-PT |
GMC (EU/mL) |
3.84 (3.00;4.91) |
191 (173;210) |
|
VR* |
|
93.8 (88.6;97.1) |
Anti-FHA |
GMC (EU/mL) |
6.17 (5.10;7.48) |
226 (208;247) |
|
VR* |
|
99.3 (96.3;100) |
#Except for GMCs and GMTs; *% participants with
post-dose 3 concentration ≥4 x LLOQ
(2 IU/mL) if pre-vaccination concentration was <4 × LLOQ or with
post-dose 3 concentration ≥pre-vaccination
concentrations if pre-vaccination concentrations
≥4 x LLOQ; ND=not determined. |
Results
A total of 177 participants were enrolled and
received at least one vaccination. Of these, 168 participants completed
the study and 156 participants were included in the PP analysis set. The
participant flow and disposition is presented in Fig. 1.
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Fig. 1 Flow of study
participants.
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Table I presents the post-dose 3 SP and VR
rates for the investigational vaccine. Table II presents
the post-dose 3 immunogenicity data for all thresholds assessed, GMCs
and GMTs post-dose 3, and geometric mean ratios, where applicable.
No immediate AR (in the 30 minutes after vaccination)
was reported after any vaccination. The frequency of solicited injection
site and systemic reactions is summarized in Table III. A
total of 60 unsolicited AEs were reported by 20.3% of participants. The
most frequently reported unsolicited AEs were upper respiratory tract
infection (24 AEs reported by 11.9% of participants); no other
unsolicited AE was reported by >10% of participants. Four SAEs were
reported in three participants (1.7%): none was considered to be related
to the vaccination. These included the death of a girl 27 days after the
second vaccination: no autopsy was performed, and this participant had
experienced 3-4 days of diarrhea with no fever or vomiting prior to
death. This death was assessed as not related to the vaccination. The
other SAEs were: an episode of severe sepsis following the first dose
with hypovolemic shock accompanied with viral lower respiratory tract
infection in the same girl who died after the second dose, an episode of
bronchopneumonia, and one episode of infantile epilepsy.
TABLE III Participants Experiencing Solicited Injection Site and Systemic Adverse Reactions Occurring
in the 7 Days after any Dose
|
Grade* |
% participants |
(95% CI) |
Any injection site reaction** |
Any |
37.9 |
(30.7; 45.6) |
Pain/Tenderness |
Any |
30.5 |
(23.7; 37.9) |
Erythema |
Any |
7.5 |
(4.0; 12.4) |
Swelling |
Any |
14.9 |
(10.0; 21.1) |
Any systemic reaction |
Any |
54.6 |
(46.9; 62.1) |
|
Grade 3 |
2.3 |
(0.6;5.8) |
Fever |
Any |
19.0 |
(13.4; 25.6) |
|
Grade 3 |
0 |
(0; 0.2) |
Vomiting |
Any |
14.9 |
(10.0; 21.1) |
|
Grade 3 |
0 |
(0; 0.2) |
Crying abnormal |
Any |
24.1 |
(18.0; 31.2) |
|
Grade 3 |
1.1 |
(0.1; 4.1) |
Drowsiness |
Any |
13.2 |
(8.6; 19.2) |
|
Grade 3 |
1.1 |
(0.1; 4.1) |
Appetite lost |
Any |
10.9 |
(6.7; 16.5) |
|
Grade 3 |
0 |
(0; 0.2) |
Irritability |
Any |
36.2 |
(29.1; 43.8) |
|
Grade 3 |
0.6 |
(0; 3.2) |
*Grade 3 fever was defined as temperature >39.5°C. Other Grade 3 systemic
symptoms were defined as: vomiting (≥6 episodes/day or requiring parenteral
hydration), crying abnormal (>3 hours), drowsiness, (sleepy most of the time
or difficult to wake up), appetite lost (missed ≥3 meals) and irritability
(inconsolable); **Grade 3 data were not calculated for injection site reactions.
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Discussion
Routine vaccination against diphtheria, tetanus,
pertussis, poliomyelitis and HB diseases using monovalent (standalone)
or combined vaccines at 6, 10 and 14 weeks of age, followed by a booster
dose at 15-18 months of age, is recommended in India. It is also
recommended to administer a first dose of HB vaccine and OPV at birth
and to administer three subsequent doses of any HB-containing vaccine at
6, 10 and 14 weeks of age, possibly concomitantly with DTP vaccinations
[15]. Participants in this infant primary series study therefore
received a total of four HB doses, i.e. at birth and 6, 10, 14
weeks of age, and three doses of DTaP-IPV-HB~PRP-T (at 6, 10, and 14
weeks of age). We documented high immunogenicity of this hexavalent
vaccine (DTaP-IPV-HB-PRP~T) in Indian infants. The 4-dose HB
administration regimen, with 1 dose given at birth (leading to a ‘1+3’
regimen) was no more reactogenic than the 3-dose administration
schedules (‘0+2+1’ or ‘0+3+1’) that have previously been assessed in
numerous studies conducted with DTaP-IPV-HB-PRP~T combined vaccines
[13,16-19]. Overall, the DTaP-IPV-HB-PRP~T vaccine was well tolerated
and there was no safety concern. Although one death occurred 27 days
after the second vaccination, this was not considered to be related to
the vaccination.
The interpretation of anti-PT and anti-FHA responses
in this study is constrained by the lack of serological correlates of
protection for aP vaccines and by the existence of several additional
factors that drive the long-term effectiveness of these vaccines. A
further limitation of the study is that, although a last dose of HB
after 24 weeks of age is recommended by the Indian Academy of
Pediatrics, no HB dose was administered after 14 weeks of age in the
present study. However, previous studies with the same vaccine have
shown that the administration of HB at birth followed by three
consecutive administrations of the DTaP-IPV-HB-PRP~T vaccine, followed
then by an additional administration of an HB vaccine (in the form of
the DTaP-IPV-HB-PRP~T vaccine) is extremely immunogenic [20-22]. No
control vaccine was used in this study as this was not required for a
licensing study in India, and since numerous randomized controlled
clinical studies had already been performed outside India during the
clinical development of the study vaccine.
These safety and immunogenicity results are
consistent with those from previous studies using the same vaccine and
conducted outside India in a range of primary series schedules
[17,18,20,21,23,24], especially when administered in the same primary
series schedule [18]. In particular, the incidence of solicited
injection site (37.9%) and systemic (54.6%) reactions was lower than
that in an earlier study in which the DTaP-IPV-HB-PRP~T vaccine was
administered in the same 6, 10, 14 week schedule with HB being given at
birth (incidences of 92.6% and 94.1%, respectively) [18].
In conclusion, this study demonstrated the
immunogenicity of DTaP-IPV-HB-PRP~T vaccine for use in the 6, 10, 14
week, 3-dose primary series in Indian infants who received standalone HB
vaccine and OPV at birth per the Indian NIP recommendations. As such,
this vaccine can be considered as an efficacious combined vaccine that
can be used for primary immunization in Indian infants.
Acknowledgement: This manuscript was formatted
with the assistance of a professional medical writer, Dr Andrew Lane
(Lane Medical Writing, France), who provided assistance in its
finalization in accordance with the European Medical Writers Association
guidelines and Good Publication Practice.
Contributors: JC and L were Principal
investigators for the study, and were responsible for its clinical
conduct, data acquisition and data interpretation; EV acted as the
Sponsor’s clinical lead and was responsible for study design, data
interpretation, and manuscript writing. All authors reviewed and
approved this manuscript.
Funding: Sanofi Pasteur, Lyon, France.
Competing interests: No clinical investigator
involved in this study received any direct payment from Sanofi Pasteur
in this regard, but received expenses for conference attendance for the
presentation of data from this study. EV is an employee of Sanofi
Pasteur.
What is Already Known?
• The
hexavalent (DTaP-IPV-HB-PRP~T) vaccine has been shown to be well
tolerated and immunogenic in many countries.
What This Study Adds?
• Primary vaccination with DTaP-IPV-HB-PRP~T vaccine is
immunogenic and safe when used in the EPI schedule (6, 10, 14
weeks) in Indian infants.
|
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