Safety and immunogenicity of the DTP/HB /Hib combination vaccine: phase I study.
Paediatrica Indonesiana
November
VOLUME 53
NUMBER 6
Original Article
Safety and immunogenicity of the DTP/HB /Hib
combination vaccine: phase I study
Kusnandi Rusmil,1 Eddy Fadlyana,1 Novilia Sjafri Bachtiar,2 Hadyana3
Abstract
Background 7KH :RUOG +HDOWK 2UJDQL]DWLRQ :+2 KDV
UHFRPPHQGHGWKHLQWURGXFWLRQRIKHSDWLWLV% +% DQGHaemophilus
influenzaW\SHE +LE YDFFLQHVLQWRURXWLQHFKLOGKRRGYDFFLQDWLRQ
SURJUDPV$QHZGLSWKHULDWHWDQXVSHUWXVVLV '73 KHSDWLWLV%+LE
pentavalent combination vaccine has been developed.
Objective To evaluate the safety and immunogenicity of a new
FRPELQDWLRQ'73+%+LEOLTXLGYDFFLQHLQLQIDQWV
Methods An open-label, uncontrolled, prospective intervention
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ZHHNV(DFKVXEMHFWUHFHLYHGGRVHVRI'73+%+LEYDFFLQH
IRUPXODWHG E\ %LR )DUPD P/ LQWUDPXVFXODUO\ DW WKH OHIW
DQWHURODWHUDO WKLJK UHJLRQ XVLQJ D JDXJH QHHGOH RI PP
OHQJWK6XEMHFWVZHUHIROORZHGIRUPRQWKDIWHUDGPLQLVWUDWLRQRI
each vaccine dose to evaluate its safety, while serum anti-diphteria,
tetanus, HB, Hib, and pertussis antibodies were measured prior
WRWKHst GRVHDQGPRQWKDIWHUWKHrd dose.
Results$PRQJYDFFLQDWHGVXEMHFWVLQIDQWVKDGIHYHUZLWKLQ
KRXUVDIWHUWKHILUVWYDFFLQDWLRQ0RVWFDVHVRIIHYHUZHUHPLOG
LQLQWHQVLW\DQGUHVROYHGZLWKLQKRXUV1RRWKHUV\VWHPLFRU
local reactions, or serious adverse events were observed in our
VXEMHFWVGXULQJWKHVWXG\7KHLPPXQRJHQLFLW\UHVXOWVDIWHUrd
vaccine dose showed that the geometric mean titer of the antiSRO\ULERV\OULELWRO SKRVSKDWH 353 DQWLERG\ OHYHOV LQFUHDVHG
VLJQLILFDQWO\IURPJP/WRJP/DIWHUYDFFLQDWLRQ
and most infants had a fourfold or greater rise in antibody levels
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+%+LE OLTXLG YDFFLQH KDG VHURSURWHFWLYH DQWLERGLHV DJDLQVW
WHWDQXV GLSKWKHULDD DQG KHSDWLWLV % ZKLOH LQIDQWV KDG
seroprotective antibodies against pertussis.
Conclusion 7KLVQHZGLSKWKHULDWHWDQXVSHUWXVLVKHSDWLWLV%+LE
combination vaccine has excellent safety profile and antibody
responses in infants. These results encourage further clinical
evaluation in phase II. [Paediatr Indones. 2013;53:309-14.].
Keywords: DTP/HB/Hib vaccine, safety,
immunogenicity, phase I
G
lobal strategies for immunization against
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sponsored Expanded Program on Immunization
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coverage with a three-dose vaccination schedule
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target has been achieved, though with considerable
regional variation within the global target. The new
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coverage with DTP vaccination of infants aged less
WKDQRQH\HDUE\WKH\HDU In countries where
hepatitis B is endemic, early infant immunization
has also been recommended. Since the coverage
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in Indonesia, a combination of HB with DTP was
considered to be a good way to increase the coverage
of HB immunization. In Indonesia, the Lombok study
ï FRQFOXGHGWKDWRIFKLOGUHQEHORZ
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6FKRRO+DVDQ 6DGLNLQ +RVSLWDO %DQGXQJ ,QGRQHVLD Surveillance &
Clinical Trial Division, BioFarma, Bandung, Indonesia, Department
(SLGHPLRORJ\ %LRVWDWLVWLFV 3DGMDGMDUDQ 8QLYHUVLW\ 0HGLFDO 6FKRRO
Hasan Sadikin Hospital, Bandung, Indonesia3.
Reprint requests to: Kusnandi Rusmil, Growth and Development Divison,
'HSDUWPHQW RI &KLOG +HDOWK 3DGMDGMDUDQ 8QLYHUVLW\ 0HGLFDO 6FKROO
+DVDQ 6DGLNLQ +RVSLWDO %DQGXQJ -O 3DVWHXU %DQGXQJ 7HO
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Paediatr Indones, Vol. 53, No. 6, November 2013309
Kusnandi Rusmil et al: 6DIHW\DQGLPPXQRJHQLFLW\RIWKH'73+%+LEFRPELQDWLRQYDFFLQH
DGGLWLRQDVWXG\UHSRUWHGWKDWLQVXEMHFWVIURPWZR
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ZHUHSRVLWLYHIRUHaemophylus influenzae.4
The limited immunogenicity of the polysacchaULGHDQWLSRO\ULERV\OULELWROSKRVSKDWH 353 YDFFLQH
in infants and young children led to the development
RIWKH+LESURWHLQFRQMXJDWHYDFFLQH&RQMXJDWLRQLV
the process of chemically bonding a polysaccharide,
a somewhat ineffective antigen, to a protein carrier,
a more effective antigen. This process changes the
polysaccharide from a T-independent to a T-dependent antigen and greatly improves immunogenicity,
particularly in young children.5 7KH+LEFRQMXJDWH
vaccine is one such vaccine that can be used as part
of EPI. It has dramatically reduced the incidence of
Hib meningitis. This vaccine is given in a schedule of
three doses during infancy, together with DPT, with or
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The aim of this trial was to assess the safety and imPXQRJHQLFLW\DIWHUWKUHHGRVHRI'73+%+LEYDFFLQH
formulated by Bio Farma.
Methods
This phase I of intervention study was conducted by
the Department of Child Health at Hasan Sadikin
+RVSLWDOIURP$SULOWR$XJXVWDWWKHSULPDU\
health center (puskesmas LQ *DUXGD %DQGXQJ
Ethical clearance was obtained from the Ethics
Committee of the Hasan Sadikin Hospital. The
clinical trial protocol and vaccine were also approved
by the Indonesian National Regulatory Affair. This
trial was conducted in accordance with the latest
Edinburgh, Scotland revision of the Declaration of
Helsinki, International Conference on Harmonisation
(,&+ *RRG&OLQLFDO3UDFWLFHJXLGHOLQHV and local
regulatory requirements. 7KH VXEMHFWV LQYROYHG
LQWKLVVWXG\ZHUHKHDOWK\LQIDQWVDJHGïZHHNV
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the nature of the study and signed the informed
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Hib vaccine contained purified diphtheria toxoid
( LQWHUQDWLRQDO XQLWV ,8 SXULILHG WHWDQXV
toxoid (,8 LQDFWLYDWHGB. pertussis whole-cell
310Paediatr Indones, Vol. 53, No. 6, November 2013
suspension ( ,8 PFJ UHFRPELQDQW +%V$J
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health center for the first three days after the first
immunization dose for adverse events. The reactions
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cards collected and confirmed by the investigators at
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DQGKRXUVDVZHOODVGD\VDIWHULPPXQL]DWLRQ
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$QWLERG\WLWHUVWR3537RU+LEGLSKWKHULDDQGWHWDnus were evaluated using the enzyme-linked immunoVRUEHQWDVVD\ (/,6$ PHWKRGDQGSHUWXVVLVDQWLERGLHV
were tested using a microagglutination method. All
four methods had been validated and were done at the
Clinical Trial Department of Bio Farma after blinding
procedure. Anti-HB antibodies were tested using a kit
from Abbott in a commercial laboratory which had
been audited by Quality Assurance from Bio Farma.
The original identity of the samples was concealed to
ensure unbiased antibody testing.
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diphtheria, tetanus, pertussis, and hepatitis B were
calculated in percentages. Protective levels of Hib
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DQGJP/IRUORQJWHUPSURWHFWLRQ For tetanus
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Seroconversion rates are calculated by the percentage
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fold antibody increase after immunization. Geometric
mean titers prior to immunization were compared to
those after immunization.
Results
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vaccine, and met the protocol criteria.
Adverse events reported after immunization
are summarized in Table 11RVXEMHFWVSUHVHQWHG
with immediate local reactions or systemic events
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VXEMHFWVSUHVHQWHGZLWKGHOD\HGV\VWHPLFHYHQWV
PDLQO\LQWKHSHULRGIURPPLQXWHVWRKRXUV
DIWHULPPXQL]DWLRQ)XUWKHUPRUHQRVXEMHFWVSUHsented with immediate local reactions or systemic
HYHQWVIURP!KRXUVWRGD\VDIWHULPPXQL]Dtion and no serious adverse events were observed
during the study.
After the 3rd LPPXQL]DWLRQ GRVH LQIDQWV
were considered to be protected against Hib, as the
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post-immunization (Table 2).
The proportions of infants who had postimmunization anti-diphtheria titers of ,8P/
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mL post-immunization. The proportions of infants
who had post-immunization anti-tetanus titers of
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respectively. The GMT of anti-tetanus antibodies
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infants underwent an anti-diphtheria transition from
seronegative to seropositive (Table 3).
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titers G/ SUHVHQWHGZLWKDQWL37WLWHUV
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Table 1. 5WOOCT[QHCFXGTUGGXGPVUHQNNQYKPIVJGſTUVFQUGQH&62*$*KDXCEEKPG
Adverse events
Immediate reactions from 0 to 30 min after immunization
Local reactions
Systemic events
Delayed adverse events from 31 min to 24 hours after immunization
Local reactions
Systemic events
Delayed adverse events from >24 to 48 hours after immunization
Local reactions
Systemic events
Delayed adverse events from >48 to 72 hours after immunization
Local reactions
Systemic events
Delayed adverse events from 72 hours to 28 days after immunization
Local reactions
Systemic events
N = 30
0
0
0
18
0
0
0
0
0
0
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YJQNGEGNN RGTVWUUKU *$ JGRCVKVKU$ *KD *CGOQRJKNWUKPƀWGP\CGVype b
Table 2. #PVKDQF[TGURQPUGUVQVJG*KDEQORQPGPVRTGCPFRQUVXCEEKPCVKQPYKVJ&62*$*KD
Antibody responses
Anti-PRP >0.15 µg/mL, n
95% CI (%)
Anti-PRP >1.0 µg/mL, n
95% CI (%)
#PVK*KD)/6zIO.
95% CI (%)
#PVKDQF[VKVGTŮHQNFKPETGCUGP
95% CI (%)
Seronegative to seropositive transition, n
95% CI (%)
Pre-vaccination
N=30
8
12.3 to 45.9
0
0 to 11.6
0.0041
0.0015 to 0.0108
-
Post-vaccination
N=30
29
82.8 to 99.9
26
69.3 to 96.2
4.37
2.0635 to 9.2858
27
73.5 to 97.9
21
50.6 to 85.3
)/6 IGQOGVTKEOGCPVKVGT %+ EQPſFGPEGKPVGTXCN
Paediatr Indones, Vol. 53, No. 6, November 2013311
Kusnandi Rusmil et al: 6DIHW\DQGLPPXQRJHQLFLW\RIWKH'73+%+LEFRPELQDWLRQYDFFLQH
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increased antibody titers (Table 4).
The proportion of infants with anti-hepatitis B
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to seropositive (Table 5).
Table 3. Serological responses to diphtheria and tetanus toxoid antigens, pre- and post- vaccination
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Antibody response
Anti-diptheria
0.01 IU/mL, n
0.1 IU/mL, n
GMT, IU/mL
95% CI for GMT
Anti-tetanus
0.01 IU/mL, n
0.1 IU/mL, n
GMT, IU/mL
95% CI for GMT
#PVKDQF[VKVGTŮHQNFKPETGCUGP
- Anti-diptheria
95% CI (%)
- Anti-tetanus
95% CI (%)
Seronegative to seropositive transition, n
- Anti-diptheria
95% CI (%)
- Anti-tetanus
Pre-vaccination
N=30
Post-vaccination
N=30
11
2
0.0031
0.0017 to 0.0058
30
28
0.259
0.2068 to 0.4233
29
25
0.5098
0.287 to 0.9057
30
27
0.480
0.3349 to 0.6891
-
28
77.9 to 99.2
5
5.6 to 34.7
19
43.9 to 80.1
n.a.
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post-booster seroconversion rates).
n.a: percentage of infants presenting with anti-tetanus transition of seronegative to seropositive is not applicable, since all the
subjects were protected before immunization
Table 4. #PVKDQF[TGURQPUGUVQVJGRGTVWUUKUEQORQPGPVRTGCPFRQUVXCEEKPCVKQPYKVJ&62*$
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Antibody response
GMT, l/dL
95% CI (%)
Anti-PT >40 (1/dL)
95% CI (%)
#PVKDQF[VKVGTŮHQNFKPETGCUGP
95% CI (%)
Pre-vaccination
N=30
11.215
9.517 to 13.213
2
0.8 to 22.1
-
Post-vaccination
N=30
148.936
104.448 to 212.3244
28
77.9 to 99.2
25
65.3 to 94.4
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Table 5.#PVKDQF[TGURQPUGUVQVJGJGRCVKVKU$EQORQPGPVRTGCPFRQUVXCEEKPCVKQPYKVJ&62*$
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Antibody response
Anti-hepatitis B >10 mIU/L
95% CI (%)
GMT, mIU/mLb
95% CI
Antibody titer 4-fold increase, n
95% CI (%)
Seronegative to seropositive transition, n
95% CI (%)
Pre-vaccination
N=30
3
2.1 to 26.5
0.0021
(0.0007 to 0.0061)
-
Post-vaccination
N=30
30
88.4 to 100
547.898
(381.5926 to 786.8646)
29
82.8 to 99.9
27
73.5 to 97.9
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312Paediatr Indones, Vol. 53, No. 6, November 2013
Kusnandi Rusmil et al: 6DIHW\DQGLPPXQRJHQLFLW\RIWKH'73+%+LEFRPELQDWLRQYDFFLQH
Discussion
The availability of combined vaccines containing
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ideally all, diseases for which universal immunization
is recommended in infancy would simplify the
implementation, increase the acceptance, reduce the
global cost of immunization programs, and improve
disease control, while offering the possibility of disease
elimination or even pathogen eradication.Vaccine
development proceeds through discovery, process
engineering, toxicology, and animal studies to human
phase I, II, and III trials. The human trials initially
focus on safety, involving small groups of people
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populations (persons close to the age and other
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to determine both safety and the stimulation of an
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target populations to establish whether a vaccine
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in our phase I trial. All participants were intensively
examined at the primary health care center during the
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I study demonstrated good safety and immunogenicity
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There were no serious local or systemic reactions
in this study. All observed reactions were slight,
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the administration of the vaccine and resolved without
medical intervention.
The anti-PRP antibody GMT significantly
increased after the 3rd YDFFLQDWLRQ GRVH J
mL , compared to the concentrations found in prevaccination sera, and most infants had a 4-fold-orJUHDWHUULVHLQDQWLERG\OHYHOVRYHUWKHLUSUHLQMHFWLRQ
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seroprotective antibodies against tetanus, diphtheria,
and hepatitis B. We observed good immunogenicity
and reactogenicity profiles for the new combined '73
+%+LEYDFFLQH
Combination vaccines have numerous advanWDJHV LQFOXGLQJ D GHFUHDVHG QXPEHU RI LQMHFWLRQV
increased compliance, better coverage, and simplified
logistics. They also result in substantial reductions in
program costs, since the indirect costs of immunizing
a child (e.g., logistics, materials involved, payment of
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combination vaccine for primary and booster vaccination study of infants in Latin America showed that
both vaccination regimens elicited excellent immune
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seroprotective anti-PRP antibody concentrations of
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was given in one shot immunization in the left thigh
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shots at the different thigh (e.e combined DTPw-HB
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was not inferior to licensed vaccines in terms of seroprotection, seropositivity, and vaccine response rates
for all component antigens. Persistence of antibodies
against all study vaccine antigens up to the time of
booster vaccination was comparable between groups,
and a marked increase of all antibody concentrations
was observed after the booster dose. Both vaccine
regimens were similar in terms of their overall reactogenicity profiles.
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pathogens and will ease the implementation of global
pediatric immunization programs, with a minimum
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coverage.
In conclusion, the excellent safety profile and
antibody responses in the infants observed during
this study encourage us to proceed to further clinical
evaluations in phase II.
References
/RRNHU & DQG .HOO\ + 1RIDXOW FRPSHQVDWLRQ IROORZLQJ
adverse events attributed to vaccination: a review of internaWLRQDOSURJUDPPHV%XOO:RUOG+HDOWK2UJDQ
:RUOG +HDOWK 2UJDQL]DWLRQ +HSDWLWLV % 9DFFLQH :+2
:NO\(SLGHPLRO5HF
*HVVQHU%'6XWDQWR$/LQHKDQ0'MHODQWLN,*)OHWFKHU
T, Gerudug IK et al. Incidences of vaccine-preventable
Haemophilus influenza type b pneumonia and meningitis in
Paediatr Indones, Vol. 53, No. 6, November 2013313
Kusnandi Rusmil et al: 6DIHW\DQGLPPXQRJHQLFLW\RIWKH'73+%+LEFRPELQDWLRQYDFFLQH
Indonesian children: hamlet-randomized vaccine-probe trial.
/DQFHW
4. Kartasamita CB, Krishna E, Murad C, Sudigdoadi S, Rendieni
Y. Haemophilus influenza serotypes distribution and antimicrobial resistance in children with non-severe pneumonia.
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of multistates surveillance study. The Bacterial meningitis
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6. International Conference on Harmonization ICH Guidance
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7. International Conference on Harmonization ICH Guideline.
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314Paediatr Indones, Vol. 53, No. 6, November 2013
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November
VOLUME 53
NUMBER 6
Original Article
Safety and immunogenicity of the DTP/HB /Hib
combination vaccine: phase I study
Kusnandi Rusmil,1 Eddy Fadlyana,1 Novilia Sjafri Bachtiar,2 Hadyana3
Abstract
Background 7KH :RUOG +HDOWK 2UJDQL]DWLRQ :+2 KDV
UHFRPPHQGHGWKHLQWURGXFWLRQRIKHSDWLWLV% +% DQGHaemophilus
influenzaW\SHE +LE YDFFLQHVLQWRURXWLQHFKLOGKRRGYDFFLQDWLRQ
SURJUDPV$QHZGLSWKHULDWHWDQXVSHUWXVVLV '73 KHSDWLWLV%+LE
pentavalent combination vaccine has been developed.
Objective To evaluate the safety and immunogenicity of a new
FRPELQDWLRQ'73+%+LEOLTXLGYDFFLQHLQLQIDQWV
Methods An open-label, uncontrolled, prospective intervention
SKDVH,VWXG\ZDVFRQGXFWHGRQKHDOWK\LQIDQWVDJHGï
ZHHNV(DFKVXEMHFWUHFHLYHGGRVHVRI'73+%+LEYDFFLQH
IRUPXODWHG E\ %LR )DUPD P/ LQWUDPXVFXODUO\ DW WKH OHIW
DQWHURODWHUDO WKLJK UHJLRQ XVLQJ D JDXJH QHHGOH RI PP
OHQJWK6XEMHFWVZHUHIROORZHGIRUPRQWKDIWHUDGPLQLVWUDWLRQRI
each vaccine dose to evaluate its safety, while serum anti-diphteria,
tetanus, HB, Hib, and pertussis antibodies were measured prior
WRWKHst GRVHDQGPRQWKDIWHUWKHrd dose.
Results$PRQJYDFFLQDWHGVXEMHFWVLQIDQWVKDGIHYHUZLWKLQ
KRXUVDIWHUWKHILUVWYDFFLQDWLRQ0RVWFDVHVRIIHYHUZHUHPLOG
LQLQWHQVLW\DQGUHVROYHGZLWKLQKRXUV1RRWKHUV\VWHPLFRU
local reactions, or serious adverse events were observed in our
VXEMHFWVGXULQJWKHVWXG\7KHLPPXQRJHQLFLW\UHVXOWVDIWHUrd
vaccine dose showed that the geometric mean titer of the antiSRO\ULERV\OULELWRO SKRVSKDWH 353 DQWLERG\ OHYHOV LQFUHDVHG
VLJQLILFDQWO\IURPJP/WRJP/DIWHUYDFFLQDWLRQ
and most infants had a fourfold or greater rise in antibody levels
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+%+LE OLTXLG YDFFLQH KDG VHURSURWHFWLYH DQWLERGLHV DJDLQVW
WHWDQXV GLSKWKHULDD DQG KHSDWLWLV % ZKLOH LQIDQWV KDG
seroprotective antibodies against pertussis.
Conclusion 7KLVQHZGLSKWKHULDWHWDQXVSHUWXVLVKHSDWLWLV%+LE
combination vaccine has excellent safety profile and antibody
responses in infants. These results encourage further clinical
evaluation in phase II. [Paediatr Indones. 2013;53:309-14.].
Keywords: DTP/HB/Hib vaccine, safety,
immunogenicity, phase I
G
lobal strategies for immunization against
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V XQGHU WKH DXVSLFHV RI WKH :+2
sponsored Expanded Program on Immunization
(3, 7KH WDUJHW ZDV WR DFKLHYH JOREDO '73
coverage with a three-dose vaccination schedule
LQ LQIDQWV DJHG OHVV WKDQ RQH \HDU E\ 7KLV
target has been achieved, though with considerable
regional variation within the global target. The new
JRDO VHW UHFHQWO\ E\ WKH :+2 LV WR DFKLHYH
coverage with DTP vaccination of infants aged less
WKDQRQH\HDUE\WKH\HDU In countries where
hepatitis B is endemic, early infant immunization
has also been recommended. Since the coverage
RI KHSDWLWLV % +% LPPXQL]DWLRQ LV PXFK ORZHU
in Indonesia, a combination of HB with DTP was
considered to be a good way to increase the coverage
of HB immunization. In Indonesia, the Lombok study
ï FRQFOXGHGWKDWRIFKLOGUHQEHORZ
\HDUVRIDJHKDG+LELQWKHLUUHVSLUDWRU\WUDFW3 In
)URPWKH'HSDUWPHQWRI&KLOG+HDOWK3DGMDGMDUDQ8QLYHUVLW\0HGLFDO
6FKRRO+DVDQ 6DGLNLQ +RVSLWDO %DQGXQJ ,QGRQHVLD Surveillance &
Clinical Trial Division, BioFarma, Bandung, Indonesia, Department
(SLGHPLRORJ\ %LRVWDWLVWLFV 3DGMDGMDUDQ 8QLYHUVLW\ 0HGLFDO 6FKRRO
Hasan Sadikin Hospital, Bandung, Indonesia3.
Reprint requests to: Kusnandi Rusmil, Growth and Development Divison,
'HSDUWPHQW RI &KLOG +HDOWK 3DGMDGMDUDQ 8QLYHUVLW\ 0HGLFDO 6FKROO
+DVDQ 6DGLNLQ +RVSLWDO %DQGXQJ -O 3DVWHXU %DQGXQJ 7HO
)D[ (PDLO NXVQDQGL#KRUPDLOFRm.
Paediatr Indones, Vol. 53, No. 6, November 2013309
Kusnandi Rusmil et al: 6DIHW\DQGLPPXQRJHQLFLW\RIWKH'73+%+LEFRPELQDWLRQYDFFLQH
DGGLWLRQDVWXG\UHSRUWHGWKDWLQVXEMHFWVIURPWZR
%DQGXQJVXEGLVWULFWVRIWKURDWVZDEVDPSOHV
ZHUHSRVLWLYHIRUHaemophylus influenzae.4
The limited immunogenicity of the polysacchaULGHDQWLSRO\ULERV\OULELWROSKRVSKDWH 353 YDFFLQH
in infants and young children led to the development
RIWKH+LESURWHLQFRQMXJDWHYDFFLQH&RQMXJDWLRQLV
the process of chemically bonding a polysaccharide,
a somewhat ineffective antigen, to a protein carrier,
a more effective antigen. This process changes the
polysaccharide from a T-independent to a T-dependent antigen and greatly improves immunogenicity,
particularly in young children.5 7KH+LEFRQMXJDWH
vaccine is one such vaccine that can be used as part
of EPI. It has dramatically reduced the incidence of
Hib meningitis. This vaccine is given in a schedule of
three doses during infancy, together with DPT, with or
ZLWKRXWDERRVWHUGRVHDWWKHDJHRIPRQWKV3,4
The aim of this trial was to assess the safety and imPXQRJHQLFLW\DIWHUWKUHHGRVHRI'73+%+LEYDFFLQH
formulated by Bio Farma.
Methods
This phase I of intervention study was conducted by
the Department of Child Health at Hasan Sadikin
+RVSLWDOIURP$SULOWR$XJXVWDWWKHSULPDU\
health center (puskesmas LQ *DUXGD %DQGXQJ
Ethical clearance was obtained from the Ethics
Committee of the Hasan Sadikin Hospital. The
clinical trial protocol and vaccine were also approved
by the Indonesian National Regulatory Affair. This
trial was conducted in accordance with the latest
Edinburgh, Scotland revision of the Declaration of
Helsinki, International Conference on Harmonisation
(,&+ *RRG&OLQLFDO3UDFWLFHJXLGHOLQHV and local
regulatory requirements. 7KH VXEMHFWV LQYROYHG
LQWKLVVWXG\ZHUHKHDOWK\LQIDQWVDJHGïZHHNV
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the nature of the study and signed the informed
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DQWHURODWHUDO WKLJK UHJLRQ XVLQJ D JDXJH QHHGOH
RIPPOHQJWK(DFKP/GRVHRIWKH'73+%
Hib vaccine contained purified diphtheria toxoid
( LQWHUQDWLRQDO XQLWV ,8 SXULILHG WHWDQXV
toxoid (,8 LQDFWLYDWHGB. pertussis whole-cell
310Paediatr Indones, Vol. 53, No. 6, November 2013
suspension ( ,8 PFJ UHFRPELQDQW +%V$J
SURWHLQPJDOXPLQXPSKRVSKDWHPJVRGLXP
FKORULGHDQGPJWKLPHURVDO SURGXFHGE\%LR
)DUPD EDWFKQXPEHU 7KHLQWHUYDORIHDFK
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6\VWHPLFDQGORFDOUHDFWLRQVZHUHHYDOXDWHGDW
PLQXWHVDQGKRXUVDVZHOODVGD\VDIWHU
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health center for the first three days after the first
immunization dose for adverse events. The reactions
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cards collected and confirmed by the investigators at
WKHVXEMHFWV·ODVWYLVLWV5HDFWLRQVDIWHUWKHVHFRQGDQG
WKLUGGRVHVZHUHUHFRUGHGRQWKHGLDU\FDUGIRU
DQGKRXUVDVZHOODVGD\VDIWHULPPXQL]DWLRQ
%ORRGVSHFLPHQVZHUHWDNHQEHIRUHWKHVWLPPXQL]DWLRQDQGGD\VDIWHUWKHODVWLPPXQL]DWLRQ
$QWLERG\WLWHUVWR3537RU+LEGLSKWKHULDDQGWHWDnus were evaluated using the enzyme-linked immunoVRUEHQWDVVD\ (/,6$ PHWKRGDQGSHUWXVVLVDQWLERGLHV
were tested using a microagglutination method. All
four methods had been validated and were done at the
Clinical Trial Department of Bio Farma after blinding
procedure. Anti-HB antibodies were tested using a kit
from Abbott in a commercial laboratory which had
been audited by Quality Assurance from Bio Farma.
The original identity of the samples was concealed to
ensure unbiased antibody testing.
7KH QXPEHU RI VXEMHFWV SURWHFWHG IURP +LE
diphtheria, tetanus, pertussis, and hepatitis B were
calculated in percentages. Protective levels of Hib
DQWLERGLHVDUHJP/IRUDVKRUWWHUPSURWHFWLRQ
DQGJP/IRUORQJWHUPSURWHFWLRQ For tetanus
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Seroconversion rates are calculated by the percentage
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VHURSRVLWLYHRUWKHSHUFHQWDJHRIVXEMHFWVZLWKIRXU
fold antibody increase after immunization. Geometric
mean titers prior to immunization were compared to
those after immunization.
Results
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PHGLDQDJHRIZHHNV)LIWHHQVXEMHFWVZHUHPDOH$OO
Kusnandi Rusmil et al: 6DIHW\DQGLPPXQRJHQLFLW\RIWKH'73+%+LEFRPELQDWLRQYDFFLQH
VXEMHFWVUHFHLYHGWKUHHGRVHVRI'73+%+LEOLTXLG
vaccine, and met the protocol criteria.
Adverse events reported after immunization
are summarized in Table 11RVXEMHFWVSUHVHQWHG
with immediate local reactions or systemic events
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VXEMHFWVSUHVHQWHGZLWKGHOD\HGV\VWHPLFHYHQWV
PDLQO\LQWKHSHULRGIURPPLQXWHVWRKRXUV
DIWHULPPXQL]DWLRQ)XUWKHUPRUHQRVXEMHFWVSUHsented with immediate local reactions or systemic
HYHQWVIURP!KRXUVWRGD\VDIWHULPPXQL]Dtion and no serious adverse events were observed
during the study.
After the 3rd LPPXQL]DWLRQ GRVH LQIDQWV
were considered to be protected against Hib, as the
JHRPHWULF PHDQ WLWHU *07 RI DQWL+LE LQFUHDVHG
IURPJP/SUHLPPXQL]DWLRQWRJP/
post-immunization (Table 2).
The proportions of infants who had postimmunization anti-diphtheria titers of ,8P/
DQG,8P/ZHUHDQGUHVSHFWLYHO\
7KH*07RIDQWLGLSKWKHULDDQWLERGLHVZDV J
mL post-immunization. The proportions of infants
who had post-immunization anti-tetanus titers of
,8P/DQG,8P/ZHUHDQG
respectively. The GMT of anti-tetanus antibodies
ZDV JP/ SRVWLPPXQL]DWLRQ )XUWKHUPRUH
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infants underwent an anti-diphtheria transition from
seronegative to seropositive (Table 3).
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G/ ZKLOH RI LQIDQWV SUHVHQWHG ZLWK DQWL37
titers G/ SUHVHQWHGZLWKDQWL37WLWHUV
G/ DQGSUHVHQWHGZLWKDQWL37WLWHUV
Table 1. 5WOOCT[QHCFXGTUGGXGPVUHQNNQYKPIVJGſTUVFQUGQH&62*$*KDXCEEKPG
Adverse events
Immediate reactions from 0 to 30 min after immunization
Local reactions
Systemic events
Delayed adverse events from 31 min to 24 hours after immunization
Local reactions
Systemic events
Delayed adverse events from >24 to 48 hours after immunization
Local reactions
Systemic events
Delayed adverse events from >48 to 72 hours after immunization
Local reactions
Systemic events
Delayed adverse events from 72 hours to 28 days after immunization
Local reactions
Systemic events
N = 30
0
0
0
18
0
0
0
0
0
0
&62 FKRJVJGTKCVGVCPWU
YJQNGEGNN RGTVWUUKU *$ JGRCVKVKU$ *KD *CGOQRJKNWUKPƀWGP\CGVype b
Table 2. #PVKDQF[TGURQPUGUVQVJG*KDEQORQPGPVRTGCPFRQUVXCEEKPCVKQPYKVJ&62*$*KD
Antibody responses
Anti-PRP >0.15 µg/mL, n
95% CI (%)
Anti-PRP >1.0 µg/mL, n
95% CI (%)
#PVK*KD)/6zIO.
95% CI (%)
#PVKDQF[VKVGTŮHQNFKPETGCUGP
95% CI (%)
Seronegative to seropositive transition, n
95% CI (%)
Pre-vaccination
N=30
8
12.3 to 45.9
0
0 to 11.6
0.0041
0.0015 to 0.0108
-
Post-vaccination
N=30
29
82.8 to 99.9
26
69.3 to 96.2
4.37
2.0635 to 9.2858
27
73.5 to 97.9
21
50.6 to 85.3
)/6 IGQOGVTKEOGCPVKVGT %+ EQPſFGPEGKPVGTXCN
Paediatr Indones, Vol. 53, No. 6, November 2013311
Kusnandi Rusmil et al: 6DIHW\DQGLPPXQRJHQLFLW\RIWKH'73+%+LEFRPELQDWLRQYDFFLQH
G/ ,QDGGLWLRQLQIDQWVKDGIROG
increased antibody titers (Table 4).
The proportion of infants with anti-hepatitis B
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*07 ZDV P,8P/ 3URSRUWLRQ RI VXEMHFWV
ZLWKLQFUHDVLQJDQWLERG\WLWHUIROGZDV DQG
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to seropositive (Table 5).
Table 3. Serological responses to diphtheria and tetanus toxoid antigens, pre- and post- vaccination
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Antibody response
Anti-diptheria
0.01 IU/mL, n
0.1 IU/mL, n
GMT, IU/mL
95% CI for GMT
Anti-tetanus
0.01 IU/mL, n
0.1 IU/mL, n
GMT, IU/mL
95% CI for GMT
#PVKDQF[VKVGTŮHQNFKPETGCUGP
- Anti-diptheria
95% CI (%)
- Anti-tetanus
95% CI (%)
Seronegative to seropositive transition, n
- Anti-diptheria
95% CI (%)
- Anti-tetanus
Pre-vaccination
N=30
Post-vaccination
N=30
11
2
0.0031
0.0017 to 0.0058
30
28
0.259
0.2068 to 0.4233
29
25
0.5098
0.287 to 0.9057
30
27
0.480
0.3349 to 0.6891
-
28
77.9 to 99.2
5
5.6 to 34.7
19
43.9 to 80.1
n.a.
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post-booster seroconversion rates).
n.a: percentage of infants presenting with anti-tetanus transition of seronegative to seropositive is not applicable, since all the
subjects were protected before immunization
Table 4. #PVKDQF[TGURQPUGUVQVJGRGTVWUUKUEQORQPGPVRTGCPFRQUVXCEEKPCVKQPYKVJ&62*$
*KDXCEEKPG
Antibody response
GMT, l/dL
95% CI (%)
Anti-PT >40 (1/dL)
95% CI (%)
#PVKDQF[VKVGTŮHQNFKPETGCUGP
95% CI (%)
Pre-vaccination
N=30
11.215
9.517 to 13.213
2
0.8 to 22.1
-
Post-vaccination
N=30
148.936
104.448 to 212.3244
28
77.9 to 99.2
25
65.3 to 94.4
)/6 IGQOGVTKEOGCPVKVGT %+ EQPſFGPEGKPVGTXCN
Table 5.#PVKDQF[TGURQPUGUVQVJGJGRCVKVKU$EQORQPGPVRTGCPFRQUVXCEEKPCVKQPYKVJ&62*$
*KDXCEEKPG
Antibody response
Anti-hepatitis B >10 mIU/L
95% CI (%)
GMT, mIU/mLb
95% CI
Antibody titer 4-fold increase, n
95% CI (%)
Seronegative to seropositive transition, n
95% CI (%)
Pre-vaccination
N=30
3
2.1 to 26.5
0.0021
(0.0007 to 0.0061)
-
Post-vaccination
N=30
30
88.4 to 100
547.898
(381.5926 to 786.8646)
29
82.8 to 99.9
27
73.5 to 97.9
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312Paediatr Indones, Vol. 53, No. 6, November 2013
Kusnandi Rusmil et al: 6DIHW\DQGLPPXQRJHQLFLW\RIWKH'73+%+LEFRPELQDWLRQYDFFLQH
Discussion
The availability of combined vaccines containing
SURWHFWLYH DQWLJHQV DJDLQVW WKH PDMRULW\ RI DQG
ideally all, diseases for which universal immunization
is recommended in infancy would simplify the
implementation, increase the acceptance, reduce the
global cost of immunization programs, and improve
disease control, while offering the possibility of disease
elimination or even pathogen eradication.Vaccine
development proceeds through discovery, process
engineering, toxicology, and animal studies to human
phase I, II, and III trials. The human trials initially
focus on safety, involving small groups of people
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populations (persons close to the age and other
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to determine both safety and the stimulation of an
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target populations to establish whether a vaccine
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in our phase I trial. All participants were intensively
examined at the primary health care center during the
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I study demonstrated good safety and immunogenicity
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There were no serious local or systemic reactions
in this study. All observed reactions were slight,
WUDQVLHQWDQGGLGQRWODVWPRUHWKDQKRXUVDIWHU
the administration of the vaccine and resolved without
medical intervention.
The anti-PRP antibody GMT significantly
increased after the 3rd YDFFLQDWLRQ GRVH J
mL , compared to the concentrations found in prevaccination sera, and most infants had a 4-fold-orJUHDWHUULVHLQDQWLERG\OHYHOVRYHUWKHLUSUHLQMHFWLRQ
OHYHOV$OOVXEMHFWVZKRUHFHLYHG'73+%+LEKDG
seroprotective antibodies against tetanus, diphtheria,
and hepatitis B. We observed good immunogenicity
and reactogenicity profiles for the new combined '73
+%+LEYDFFLQH
Combination vaccines have numerous advanWDJHV LQFOXGLQJ D GHFUHDVHG QXPEHU RI LQMHFWLRQV
increased compliance, better coverage, and simplified
logistics. They also result in substantial reductions in
program costs, since the indirect costs of immunizing
a child (e.g., logistics, materials involved, payment of
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combination vaccine for primary and booster vaccination study of infants in Latin America showed that
both vaccination regimens elicited excellent immune
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seroprotective anti-PRP antibody concentrations of
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was given in one shot immunization in the left thigh
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shots at the different thigh (e.e combined DTPw-HB
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ULJKWWKLJK 7KHFRPELQHG'73Z+%+LEYDFFLQH
was not inferior to licensed vaccines in terms of seroprotection, seropositivity, and vaccine response rates
for all component antigens. Persistence of antibodies
against all study vaccine antigens up to the time of
booster vaccination was comparable between groups,
and a marked increase of all antibody concentrations
was observed after the booster dose. Both vaccine
regimens were similar in terms of their overall reactogenicity profiles.
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pathogens and will ease the implementation of global
pediatric immunization programs, with a minimum
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coverage.
In conclusion, the excellent safety profile and
antibody responses in the infants observed during
this study encourage us to proceed to further clinical
evaluations in phase II.
References
/RRNHU & DQG .HOO\ + 1RIDXOW FRPSHQVDWLRQ IROORZLQJ
adverse events attributed to vaccination: a review of internaWLRQDOSURJUDPPHV%XOO:RUOG+HDOWK2UJDQ
:RUOG +HDOWK 2UJDQL]DWLRQ +HSDWLWLV % 9DFFLQH :+2
:NO\(SLGHPLRO5HF
*HVVQHU%'6XWDQWR$/LQHKDQ0'MHODQWLN,*)OHWFKHU
T, Gerudug IK et al. Incidences of vaccine-preventable
Haemophilus influenza type b pneumonia and meningitis in
Paediatr Indones, Vol. 53, No. 6, November 2013313
Kusnandi Rusmil et al: 6DIHW\DQGLPPXQRJHQLFLW\RIWKH'73+%+LEFRPELQDWLRQYDFFLQH
Indonesian children: hamlet-randomized vaccine-probe trial.
/DQFHW
4. Kartasamita CB, Krishna E, Murad C, Sudigdoadi S, Rendieni
Y. Haemophilus influenza serotypes distribution and antimicrobial resistance in children with non-severe pneumonia.
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$XJXVW$WKHQV*UHHFH
:HQJHU-'+LJKWRZHU$:)DFNODP55*DYHQWD6%URRPH
&9%DFWHULDOPHQLQJLWLVLQWKH8QLWHG6WDWHV 5HSRUW
of multistates surveillance study. The Bacterial meningitis
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7. International Conference on Harmonization ICH Guideline.
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