DTPa-HBV-IPV/Hib for Infants—Fong-Seng Lim et al 801

Original Article

Primary Vaccination of Infants Against Hepatitis B can be Completed Using a

Combined Hexavalent Diphtheria-tetanus-acellular pertussis-hepatitis
B-inactivated poliomyelitis-Haemophilus influenzae Type B Vaccine†
Fong-Seng Lim,1MD, Htay-Htay Han,2MD, Jeanne-Marie Jacquet,3PhD, Hans L Bock,2MD

Abstract
Introduction: Children in Singapore receive vaccination against hepatitis B virus (HBV) at 0,
1 and 5 or 6 months of age, and vaccination against pertussis, diphtheria, tetanus, and polio at
3, 4 and 5 months of age. Parents often choose to vaccinate with the combined acellular-pertussis-
inactivated polio-Hib vaccine (DTPa-IPV/Hib). We investigated whether a combined hexavalent
vaccine, DTPa-HBV-IPV/Hib, could replace the separate administration of DTPa-IPV/Hib and
HBV for the final vaccination at 5 months of age (Trial DTPa-HBV-IPV-075). Materials and
Methods: In an open study, 150 children were randomised to complete their vaccination schedule
with DTPa-IPV/Hib + HBV or DTPa-HBV-IPV/Hib. Results: One month after the final
vaccination, there was no difference between groups in seroprotection rates or antibody
concentrations against HBV. Seroprotection rates against diphtheria, tetanus, Hib and polio, as
well as vaccine response rates to pertussis antigens were also similar between groups. Local and
general symptoms occurred at a similar rate after the third dose of either vaccine. Conclusion:
The immunogenicity and reactogenicity of the hexavalent vaccine DTPa-HBV-IPV/Hib (Infanrix
hexa, GSK) group is comparable to that of separately administered DTPa-IPV/Hib and HBV
vaccines. Combined hexavalent vaccine, DTPa-HBV-IPV/Hib, could replace the separate admin-
istration of DTPa-IPV/Hib and HBV for vaccination at 5 months of age, thereby reducing the
number of injections required.
Ann Acad Med Singapore 2007;36:801-6

Key words: Combined vaccine, Hepatitis B vaccine, Hexavalent vaccine

Introduction A significant number of parents choose instead to pay to

Before the introduction of mass vaccination of newborns immunise their children with combined acellular pertussis
against hepatitis B virus (HBV) in 1987, almost 10% of vaccines also available in Singapore. The features of
children <6 years of age and almost 55% of adults showed combined diphtheria-tetanus-acellular pertussis-inactivated
evidence of HBV infection in Singapore.1 Like other Asian poliomyelitis-Haemophilus influenzae type b vaccine
countries, the primary mode of HBV transmission in (DTPa-IPV/Hib) that appeal to parents and practitioners
Singapore was perinatal.1,2 Interruption of perinatal include: fewer adverse reactions after vaccination compared
transmission through vaccination at birth has had a major to whole-cell pertussis preparations,5 the inclusion of IPV,
effect on the epidemiology of HBV in Singapore, with thereby avoiding the rare but potentially devastating
marked reductions in the incidence of acute HBV disease complication of vaccine-associated paralytic polio
and in chronic carrier rates.1,3,4 associated with the use of oral polio vaccines; the inclusion
In Singapore, monovalent HBV vaccines are administered of Hib protection; and finally but perhaps of most
at birth and at 1 and 5 or 6 months of age. Whole-cell based significance to parents and practitioners, the provision of
pertussis and oral polio vaccines are provided free for the DTPa, Hib and IPV in a single injection.
routine vaccination of infants at 3, 4 and 5 months of age. Although the use of DTPa-IPV/Hib vaccine for routine

1
National Health Care Group Polyclinics, Choa Chu Kang, Singapore
2
GlaxoSmithKline Biologicals, Singapore
3
GlaxoSmithKline Biologicals, Belgium
Address for Correspondence: Dr Fong-Seng Lim, National Health Care Group Polyclinics, Level 6, Tan Tock Seng Hospital, Singapore 688846.
Email: Fong_Seng_LIM@nhgp.com.sg
† This study was carried out at the National Health Care Group Polyclinics, Choa Chu Kang, 2 Teck Whye Cresent, #01-00, Singapore 688846
Clinical Trials Registration: www.clinicaltrials.gov NCT00366366.

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802 DTPa-HBV-IPV/Hib for Infants—Fong-Seng Lim et al

vaccination reduces the number of injections required at toxin (PT), 25 μg filamentous haemagglutinin (FHA), 8 μg
each visit, an additional injection with HBV continues to be pertactin (PRN), 40D, 8D and 32D antigen units of
needed at either the fifth or sixth month when infants poliovirus types 1, 2 and 3 respectively, reconstituted with
receive their final HBV immunisation. The combined 10 μg Hib polyribosyl-ribitol-phosphate (PRP) conjugated
hexavalent DTPa-HBV-IPV/Hib vaccine builds on the to tetanus toxoid. The DTPa-HBV-IPV/Hib (Infanrix hexa)
features of DTPa-IPV/Hib, with the additional inclusion of contained identical antigen components to the DTPa-IPV/
HBV in the vaccine formulation. We examined the Hib vaccine along with 10 μg recombinant HBsAg.
immunogenicity and reactogenicity of the hexavalent All vaccines were administered into the antero-lateral
vaccine when used at 5 months of age in the Singapore region of the thigh. DTPa-containing vaccines were given
vaccination schedule. on the left side and HBV vaccine on the right side.
Materials and Methods
Assessment of Immunogenicity
This study was conducted according to Good Clinical
Two blood samples were collected from all subjects at 3
Practice and the Declaration of Helsinki. The protocol was
months of age prior to administration of the first dose of
approved by the Ethics Committee of the KK Women’s and
DTPa-IPV/Hib, and 1 month after the final vaccination.
Children’s Hospital. Written informed consent was obtained
Samples were stored at -20ºC until shipment.
from each parent/guardian prior to the subject’s entry into
the study. Anti-diphtheria and anti-tetanus, anti-PT, anti-FHA, anti-
PRN antibodies and anti-HBV surface antibody (HBs)
This was an open study conducted in a single centre in
were measured by ELISA. Antibodies against the 3 polio
Singapore. Healthy infants were randomised into 1 of 2
virus types were measured by a virus micro-neutralisation
groups that differed only in the vaccine they received at the
assay.6 For diphtheria, tetanus, HBV and polio, antibody
final vaccination visit. All subjects received HBV
concentrations/titres equal to or above the assay cut-off
vaccination at birth and at 1 month of age, as well as DTPa-
were considered to be indicative of seroprotection. The
IPV/Hib vaccine at 3 months and 4 months of age. At 5
cut-offs for each assay were 0.1 IU/mL for diphtheria and
months of age, subjects in Group DTPa-IPV/Hib + HBV
tetanus, 10 mIU/mL for HBV and 1/8 dilution for polio
received a third and final dose of DTPa-IPV/Hib and HBV
types 1, 2 and 3. Since the assay cut-off for the diphtheria
vaccines as separate injections, while subjects in Group
ELISA assay is conservatively set at 0.1 IU/mL, subjects
DTPa-HBV-IPV/Hib received the combined hexavalent
seronegative to anti-diphtheria antibodies by ELISA testing
vaccine DTPa-HBV-IPV/Hib. The study was conducted
1 month after the last vaccination were re-tested using a
in an open fashion because the 2 groups received a different
more sensitive in vitro neutralisation assay on Vero cells,
number of vaccines at the final visit.
with a cut-off of 0.016 IU/mL.
Healthy infants 11 to 17 weeks of age at the time of the
The cut-off for anti-pertussis antibodies was 5 EL.U/mL;
first dose of DTPa-IPV/Hib were eligible for enrolment if
however, as there is no established correlate of protection
they had received routine HBV vaccination at birth and at
against pertussis a vaccine response was defined as the
1 month of age. Infants were excluded if they had received,
appearance of antibodies in initially seronegative subjects,
or planned to use any other vaccines or investigational
or the maintenance of antibody concentrations in subjects
product, within 30 days preceding the first dose of the study
seropositive prior to vaccination.
vaccine, had a family history of hereditary immuno-
deficiency, immunosuppressive conditions including All antibody testing, with the exception of the
iatrogenic immunodeficiency, major congenital defects, or neutralisation assay on Vero cells, was performed at MEP
acute disease at the time of enrolment, had received or (Michael E Pichichero) laboratories (University of
planned to receive any blood products including immuno- Rochester). The measurement of neutralising antibodies to
globulin since birth or during the study period, had allergic diphtheria was performed at a GSK laboratory in Belgium.
disease likely to be exacerbated by any component of the
Assessment of Reactogenicity
vaccine, or any neurological disorders.
Local symptoms of pain, redness and swelling, and
Vaccines systemic symptoms of drowsiness, fever (axillary
All vaccines administered during the study were temperature ≥37.5°C), irritability/fussiness and loss of
manufactured by GlaxoSmithKline (GSK) Biologicals appetite were actively solicited for 4 days following each
(Rixensart, Belgium). Each dose of HBV vaccine (Engerix- vaccination (Day 0 to 3). Symptoms that occurred were
B) contained 10 μg recombinant HBV surface antigen graded by the investigator on a 3-point scale where “Grade
(HBsAg). The DTPa-IPV/Hib vaccine contained ≥30 IU 3” was defined as: cries when limb is moved/spontaneously
diphtheria toxoid, ≥40 IU tetanus toxoid, 25 μg pertussis painful (pain); a diameter >20 mm (swelling and redness);

Annals Academy of Medicine

 DTPa-HBV-IPV/Hib for Infants—Fong-Seng Lim et al 803

axillary temperature >39.0°C (fever); crying that could not seroprotection rate of 95%, the expected 95% CI was [86.0;
be comforted/prevented normal activity (irritability/ 98.4].
fussiness); not eating at all (loss of appetite); preventing
normal activity (all other symptoms). All other symptoms Results
that occurred within 30 days of each vaccination were One hundred and fifty subjects were enrolled between
recorded. Serious adverse events were recorded from the September 2001 and September 2002. One subject (Group
first dose of DTPa-IPV/Hib until 30 days after the last DTPa-HBV-IPV/Hib) did not complete the study after
vaccination. migrating from the study area after Dose 1. Twenty-three
subjects (14 in Group DTPa-HBV-IPV/Hib) were
Statistical Analysis eliminated from the ATP cohort for immunogenicity. The
All analyses were descriptive. At each blood sampling reasons for their elimination were: being older than the
time point, antibody seroprotection/seropositivity rates protocol-defined age limit at enrolment (1 subject), having
against all vaccine antigen components were computed received medication forbidden by the protocol during the
with 95% confidence intervals (CI). Vaccine responses to study period (1 subject), non-compliance with the
pertussis antigens were calculated with 95% CI at the post- vaccination schedule (17 subjects) and non-compliance
vaccination time point. Antibody geometric mean with the blood sampling schedule or insufficient sample for
concentrations/titres (GMC/T) with 95% CI were calculated testing (4 subjects). A total of 66 and 61 subjects in group
by taking the log-transformation of individual DTPa-IPV/Hib + HBV and DTPa-HBV-IPV/Hib
concentrations/titres and calculating the anti-log of the respectively were included in the analysis of immuno-
mean of these transformed values. Antibody concentrations/ genicity. The demographic characteristics of the Total and
titres below the cut-off of the assay were given an arbitrary ATP cohorts are summarised in Table 1.
value of half the cut-off.
Immunogenicity
The incidence and intensity of individual solicited
symptoms over the 4-day follow-up period and the incidence Anti-HBs antibody response: All subjects received 2
of unsolicited symptoms within 30 days of vaccination doses of HBV vaccine (at birth and at 1 month of age) at the
were tabulated with 95% CI. Serious adverse events and time of the first blood sample collected at 3 months of age.
discontinuation due to adverse events were described As a result, almost 70% of subjects in both groups had
in detail. seroprotective anti-HBs antibody concentrations at 3 months
of age (Table 2). This increased to at least 96.7% 1 month
The analysis of immunogenicity was performed on the
after the completion of primary vaccination in both groups.
according-to-protocol (ATP) cohort for immunogenicity.
The analysis of safety was performed on the total cohort. Response to other vaccine antigens: One month after
completion of the primary vaccination course, at least 98%
With a sample size of 75 infants per group and anti-HBs

Table 1. Demographic Characteristics of the Total Cohort and the ATP Cohort for Immunogenicity

Total cohort (N = 150) ATP cohort for immunogenicity (N = 127)

Total Female Age (weeks) Total Female Age (weeks)
Group N n Mean SD Min Max N n Mean SD Min Max
DTPa-IPV/Hib + HBV 75 38 12.8 0.84 12 17 66 32 12.8 0.87 12 17
DTPa-HBV-IPV/Hib 75 47 13.0 1.07 12 18 61 42 12.9 0.90 12 16
Max: maximum age; Min: minimum age; N: number in the relevant cohort; n: number of female subjects; SD: standard deviation

Table 2. Hepatitis B Antibody Seroprotection Rates and GMCs in Subjects Vaccinated with HBV Vaccine at Birth and 1 Month of Age, Followed By
a Dose of Either HBV or DTPa-HBV-IPV/Hib Vaccine at 5 Months of Age (ATP Cohort for Immunogenicity)

Group DTPa-IPV/Hib + HBV DTPa-HBV-IPV/Hib

Antibody Time-point n %SP 95% CI GMC 95% CI n %SP 95% CI GMC 95% CI
Anti-HBs Pre 46 69.6 54.2 82.3 30.6 18.7 50.1 41 68.3 51.9 81.9 29.7 17.9 49.2
≥10 mIU/mL Post 66 98.5 91.8 100.0 938.1 606.6 1450.7 60 96.7 88.5 99.6 1128.6 722.4 1763.1
95% CI: 95% confidence interval; %SP: percent of subjects with antibody concentration above the specified cut-off; GMC: geometric mean concentration;
n: number of subjects with available results; Pre, Post: blood sample collected at 3 months of age (corresponding to 2 months after the second dose of HBV
vaccine) and 1 month after completion of primary vaccination at 6 months of age

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804 DTPa-HBV-IPV/Hib for Infants—Fong-Seng Lim et al

of subjects in both groups had seroprotective antibody Reactogenicity: All subjects returned completed symptom
concentrations against Hib, tetanus, diphtheria (by ELISA sheets after each vaccine dose they received. Since all
or neutralisation assay on Vero cells), and polio types 1, 2 subjects received the DTPa-IPV/Hib vaccine for Doses 1
and 3 (Table 3). All subjects who received the DTPa-HBV- and 2, only data concerning symptoms that followed Dose
IPV/Hib vaccine for the third dose had a vaccine response 3 are presented.
to PT, FHA and PRN. Pain, redness and swelling occurred in up to 16.2% of
Antibody GMCs for all vaccine antigens were similar vaccinees after Dose 3 and the incidence of all local
after the third vaccination, evidenced by overlapping 95% symptoms was similar in subjects who had received the
CIs, with the exception of the diphtheria antibodies, which DTPa-IPV/Hib + HBV vaccines and in those who had
were significantly higher in subjects in Group DTPa-IPV/ received the DTPa-HBV-IPV/Hib vaccine (overlapping
Hib + HBV (95% CIs did not overlap). 95% CIs in all cases, Table 4). No local symptoms of grade
Total cohort analysis: As 15% of the enrolled subjects 3 intensity occurred after Dose 3 in any subject.
were eliminated from the ATP cohort for immunogenicity, Irritability was the most commonly reported systemic
a second supplementary analysis of the Total cohort was symptom that occurred after vaccination at Dose 3
performed. The results of the analysis of the Total cohort (Table 5). The incidence of systemic symptoms was similar
were consistent with that of the ATP analysis with the between groups (overlapping 95% CIs). Grade 3 symptoms
exception of the diphtheria response: in the Total cohort were rare and only occurred in 2 subjects, both of whom
analysis the 95% CIs of the anti-diphtheria antibody GMCs were in Group DTPa-IPV/Hib + HBV.
overlapped, suggesting that a true difference between When all doses are considered, 57.3% and 54.7% of
groups may not exist. It should be noted that this study was subjects in Group DTPa-IPV/Hib + HBV and DTPa-HBV-
not powered to detect differences between groups. IPV/Hib respectively were followed by an unsolicited

Table 3. Antibody Seroprotection/Vaccine Response Rates and GMC/Ts Following Primary Vaccination (ATP Cohort for Immunogenicity)

Group DTPa-IPV/Hib + HBV Group DTPa-HBV-IPV/Hib

Antibody Timing n %SP/VR GMC/T 95% CI n %SP/VR GMC/T 95% CI
Hib Pre 64 57.8 0.2 0.1 0.2 61 52.5 0.2 0.1 0.2
≥0.015 μg/mL Post 66 100.0 6.6 5.3 8.2 61 100.0 8.4 7.0 10.1
Diphtheria Pre 63 17.5 0.1 0.1 0.1 61 18.0 0.1 0.1 0.1
≥0.016 IU/mL * Post 64 100.0 1.2 0.9 1.5 61 98.4 0.6 0.4 0.8
Tetanus Pre 64 46.9 0.1 0.1 0.2 61 59.0 0.1 0.1 0.2
≥0.1 IU/mL Post 66 98.5 3.8 3.1 4.7 61 100.0 4.2 3.5 5.0
PT Pre 64 - 3.1 2.7 3.5 61 - 2.8 2.6 3.1
VR Post 63 96.8 38.1 31.4 46.3 61 100.0 45.0 38.0 53.4
FHA Pre 64 - 3.5 3.0 4.1 61 - 3.5 3.0 4.0
VR Post 63 98.4 85.6 74.8 98.1 61 100.0 86.4 77.8 95.9
PRN Pre 64 - 3.1 2.6 3.5 61 - 2.9 2.6 3.2
VR Post 64 96.9 175.0 144.1 212.4 61 100.0 156.2 131.7 185.2
Polio 1 Pre 58 58.6 10.0 7.6 13.2 61 62.3 9.7 7.6 12.4
≥1:8 Post 62 100.0 696.3 537.2 902.5 61 100.0 711.6 535.9 945.0
Polio 2 Pre 58 48.3 9.8 7.1 13.7 61 67.9 10.9 8.5 14.0
≥1:8 Post 62 98.4 423.5 318.8 562.5 61 100.0 491.8 382.4 632.5
Polio 3 Pre 58 27.6 6.3 4.9 8.1 61 20.8 5.5 4.5 6.7
≥1:8 Post 62 98.4 1138.8 829.1 1564.1 61 100.0 1606.8 1281.5 2014.6
95% CI: 95% confidence interval; %SP/VR: percent of subjects with antibody concentrations/titre above the specified cut-off or a vaccine response for PT,
FHA, PRN; GMC/T: geometric mean antibody concentrations/titre; n: number of subjects with available results; Pre: prior to vaccination with a DTPa-
based vaccine; Post: 1 month following the final vaccination
Vaccine response defined as: post-vaccination antibody concentration ≥5 EL.U/mL for initially seronegative subjects, or maintenance of antibody
concentrations in initially seropositive subjects

Annals Academy of Medicine

 DTPa-HBV-IPV/Hib for Infants—Fong-Seng Lim et al 805

Table 4. Incidence of Solicited Local Symptoms Reported During the 4-day Follow-up Period after Dose 3 (Total Cohort)

Symptom Injection site DTPa-IPV/Hib + HBV (n = 75) DTPa-HBV-IPV/Hib (n = 74)*

n % 95% CI n % 95% CI
Pain At any injection site Any 10 13.3 6.6 23.2 7 9.5 3.9 18.5
>20 mm 0 0.0 0.0 4.8 0 0.0 0.0 4.9
DTPa-IPV/Hib Any 10 13.3 6.6 23.2
>20 mm 0 0.0 0.0 4.8 - - - -
DTPa-HBV-IPV/Hib Any - - - - 7 9.5 3.9 18.5
>20 mm - - - - 0 0.0 0.0 4.9
HBV Any 9 12.0 5.6 21.6 - - - -
>20 mm 0 0.0 0.0 4.8 - - - -
Redness At any injection site Any 12 16.0 8.6 26.3 9 12.2 5.7 21.8
>20 mm 0 0.0 0.0 4.8 0 0.0 0.0 4.9
DTPa-IPV/Hib Any 12 16.0 8.6 26.3 - - - -
>20 mm 0 0.0 0.0 4.8 - - - -
DTPa-HBV-IPV/Hib Any - - - - 9 12.2 5.7 21.8
>20 mm - - - - 0 0.0 0.0 4.9
HBV Any 10 13.3 6.6 23.2 - - - -
>20 mm 0 0.0 0.0 4.8 - - - -
Swelling At any injection site Any 5 6.7 2.2 14.9 12 16.2 8.7 26.6
>20 mm 0 0.0 0.0 4.8 0 0.0 0.0 4.9
DTPa-IPV/Hib Any 5 6.7 2.2 14.9 - - - -
>20 mm 0 0.0 0.0 4.8 - - - -
DTPa-HBV-IPV/Hib Any - - - - 12 16.2 8.7 26.6
>20 mm - - - - 0 0.0 0.0 4.9
HBV Any 5 6.7 2.2 14.9 - - - -
>20 mm 0 0.0 0.0 4.8 - - - -
Both groups received DTPa-IPV/Hib for Dose 1 and 2. Grade “3” pain: Cried when limb was moved/ spontaneously painful; 95% CI: 95% confidence
interval; %: percentage of subjects reporting a specified symptom; n: number of subjects who received Dose 3
* One subject dropped out before Dose 3.

Table 5. Incidence of Solicited General Symptoms Reported During the 4-day Follow-up Period after Dose 3 (Total Cohort)

Symptom DTPa-IPV/Hib + HBV (n = 75) DTPa-HBV-IPV/Hib (n = 74)*

n % 95% CI n % 95% CI
Drowsiness Any 15 20.0 11.6 30.8 5 6.8 2.2 15.1
Grade “3” 0 0.0 0.0 4.8 0 0.0 0.0 4.9
Irritability Any 19 25.3 16.0 36.7 14 18.9 10.7 29.7
Grade “3” 1 1.3 0.0 7.2 0 0.0 0.0 4.9
Loss of appetite Any 14 18.7 10.6 29.3 8 10.8 4.8 20.2
Grade “3” 0 0.0 0.0 4.8 0 0.0 0.0 4.9
Temperature ≥37.5° C 9 12.0 5.6 21.6 9 12.2 5.7 21.8
(axillary) >39.0° C 1 1.3 0.0 7.2 0 0.0 0.0 4.9
95% CI: 95% confidence interval; n: number of subjects who received Dose 3; n/%: number/percentage of subjects reporting a specified symptom
Both groups received DTPa-IPV/Hib for Dose 1 and 2. Grade “3” – drowsiness: drowsiness that prevented normal activity, irritability: crying that
could not be comforted/prevented normal activity, loss of appetite: Not eating at all
*One subject dropped out before Dose 3.

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806 DTPa-HBV-IPV/Hib for Infants—Fong-Seng Lim et al

symptom within 30 days after vaccination. None were of the hexavalent vaccine DTPa-HBV-IPV/Hib (Infanrix
grade 3 intensity and none were considered by the hexa) was comparable to that of separately administered
investigator to be causally related to vaccination, with the DTPa-IPV/Hib and HBV vaccines. The combined
exception of 1 case in each group of injection site reaction. hexavalent vaccine, DTPa-HBV-IPV/Hib, could replace
Seven serious adverse events occurred in 6 subjects from separate administration of DTPa-IPV/Hib and HBV for
Dose 1 until 30 days after the last vaccination, of which 6 vaccination at 5 months of age, thereby reducing the
were reported after a dose of DTPa-IPV/Hib and 1 after a number of injections required.
dose of DTPa-HBV-IPV/Hib. These events consisted of
Acknowledgement
bronchitis (2 cases in 1 subject), urinary tract infection (1
This study was funded by GlaxoSmithKline Biologicals, Rixensart, Belgium.
case), gastroenteritis (2 cases), bronchiolitis (1 case) and
head injury (1 case). None of these events were considered
by the investigator to have a causal relationship to
vaccination.

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Annals Academy of Medicine