Combined DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and <i>Haemophilus influenzae</i> B (HIB)

Edna S Bar‐On; Elad Goldberg; Sarah Hellmann; Leonard Leibovici

doi:10.1002/14651858.CD005530.pub3

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Figure 1

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Funnel plot of comparison: 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, outcome: 1.1 Anti‐PRP titres below the assay cut‐off 0.15 µg/ml.

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Figure 4

Funnel plot of comparison: 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, outcome: 1.2 Anti‐PRP titres below the assay cut‐off 1.0 µg/ml.

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Analysis 1.1

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 1 Anti‐PRP titres below the assay cut‐off 0.15 µg/ml.

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Analysis 1.2

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 2 Anti‐PRP titres below the assay cut‐off 1.0 µg/ml.

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Analysis 1.3

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 3 Anti‐FHA (Filamentous haemagglutinin).

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Analysis 1.4

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 4 Anti‐PRN (Pertactin).

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Analysis 1.5

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 5 Anti‐HBV (Hepatitis B).

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Analysis 1.6

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 6 Anti‐BPT (Pertussis).

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Analysis 1.7

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 7 Anti‐D (Diphtheria).

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Analysis 1.8

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 8 Anti‐T (Tetanus).

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Analysis 1.9

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 9 DTPa Anti‐polio type 1 below the assay cut‐off 1:8 IU/mL.

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Analysis 1.10

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 10 DTPa Anti‐polio type 2 below the assay cut‐off 1:8 IU/mL.

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Analysis 1.11

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 11 DTPa Anti‐polio type 3 below the assay cut‐off 1:8 IU/mL.

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Analysis 1.12

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 12 Serious adverse events.

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Analysis 1.13

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 13 Pain.

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Analysis 1.14

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 14 Redness.

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Analysis 1.15

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 15 Swelling.

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Analysis 1.16

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 16 Fever.

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Analysis 1.17

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 17 Fussiness or restlessness.

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Analysis 1.18

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 18 Drowsiness.

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Analysis 1.19

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 19 Irritability or tenderness.

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Analysis 1.20

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 20 Poor appetite.

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Analysis 1.21

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 21 Vomiting.

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Analysis 1.22

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 22 Diarrhoea.

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Analysis 1.23

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 23 Unusual crying.

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Analysis 1.24

Comparison 1 DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines, Outcome 24 Sleeping more than usual.

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Table 1. Serious adverse events (DTPw): details

Combined group	Separate group	Not given
A few hours after the first vaccine dose, 1 child experienced seizures, which resolved spontaneously 2 weeks after the first vaccine dose, another child was diagnosed with acute bronchiolitis and subsequently died due to respiratory distress (Faingezicht 2002)	1 acute bronchiolitis case, due to respiratory syncytials virus infection, occurred 3 days after the first vaccination. The child recovered after treatment and hospitalisation (Faingezicht 2002)	5 participants were hospitalised or experienced a serious adverse event, including 1 participant who died as a secondary result of sudden infant death syndrome 52 days after the first dose vaccine (Greenberg 2000)
3 events: one hypotonic‐hyporesponsiveness, 2 seizures (Nolan 2001)	3 events of seizures (Nolan 2001)
In 1 case 4 booster doses were followed by unsolicited grade '3' symptoms (pharyngitis and severe asthma) (Santos 2002)
12 serious adverse events were reported by 10 participants (Tregnaghi 2006)	2 serious adverse events after the primary vaccination course were reported by 2 participants (Tregnaghi 2006)
4 serious adverse events occurred in subjects receiving DTPw‐HBV/HIB 2.5 vaccine. 2 hypotonic‐hyporesponsive episodes (HHE) in HIB‐078 and 2 cases of convulsions in HIB‐079. All 4 participants recovered (Ortega‐Barria 2007)	2 events occurred following the administration of Tritanrix™‐Hep B and Hiberix™ vaccines in HIB‐078. 1 case of HHE and one case of viral meningoencephalitis (Ortega‐Barria 2007).
2 siblings (twins) presented with symptoms of fever and decreased feeding 17 days after the second dose of vaccine (Shan 5) with one of them progressing to seizures. A diagnosis of septicaemia with meningitis was made. Another infant presented 10 days after the first dose of Shan 5 with symptoms of fever, irritability and breathlessness, a condition which upon investigation was diagnosed as bronchiolitis (Rao 2009)
DTPw‐HBV/HIB: diphtheria, tetanus, whole cell pertussis/hepatitis B virus/H. influenzae type B HHE: hypotonic‐hyporesponsive episode

Table 1. Serious adverse events (DTPw): details

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Table 2. Serious adverse events (DTPa): details

Combined group	Separate group	Not given
7 SAEs were hospitalisations due to vaccination‐related common childhood infections (Avdicova 2002). 10 SAEs including one drop‐out following a serious adverse event and another following a non‐serious adverse event (Gabutti 2004). 1 case of large, local reactions after the second and third injections (Mallet 2000)	11 SAEs were hospitalisations due to vaccination‐related common childhood infections (1 erythematous rash) (Avdicova 2002). 10 SAEs including one drop‐out following a serious adverse event (Gabutti 2004). 3 infants presented symptoms that were considered as a contradiction for further vaccination:inconsolable crying i.e. more than three hours after first dose (n = 1), second dose (n = 1) and third dose (n = 1) (Mallet 2000)	2 episodes of "inconsolable crying" were reported within the context of multiple severe local reactions without further sequelae (Mallet 2000). 4 serious adverse events were reported (Aristegui 2003). 8 serious adverse events occurred (Schmitt 2000)
	1 SAE was assessed as probably related to vaccination, a hypotonic hyporesponsive episode (Marshall 2010)	26 SAEs were reported during the study. All were considered unrelated to vaccination by the investigators (Marshall 2010)
n: Number of participants SAEs: Serious Adverse Events

Table 2. Serious adverse events (DTPa): details

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Comparison 1. DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Anti‐PRP titres below the assay cut‐off 0.15 µg/ml Show forest plot	15	4272	Risk Ratio (M‐H, Random, 95% CI)	1.82 [0.98, 3.38]

1.1 DTPa titres below the assay cut‐off 0.15 µg/ml	8	2068	Risk Ratio (M‐H, Random, 95% CI)	2.60 [1.33, 5.08]
1.2 DTPw titres below the assay cut‐off 0.15 µg/ml	7	2204	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.10, 1.70]
2 Anti‐PRP titres below the assay cut‐off 1.0 µg/ml Show forest plot	15	5269	Risk Ratio (M‐H, Random, 95% CI)	1.43 [0.98, 2.10]

2.1 DTPa titres below the assay cut‐off 1.0 µg/ml	8	2060	Risk Ratio (M‐H, Random, 95% CI)	2.14 [1.48, 3.10]
2.2 DTPw titre below the assay cut‐off 1.0 µg/ml	7	3209	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.44, 1.58]
3 Anti‐FHA (Filamentous haemagglutinin) Show forest plot	8	1915	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.20, 4.36]

3.1 DTPa ‐ immunogenicity failure	8	1915	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.20, 4.36]
4 Anti‐PRN (Pertactin) Show forest plot	8	1931	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.34, 1.50]

4.1 DTPa ‐ immunogenicity failure	8	1931	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.34, 1.50]
5 Anti‐HBV (Hepatitis B) Show forest plot	19	5874	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.76, 2.01]

5.1 DTPa ‐ immunogenicity failure	9	2300	Risk Ratio (M‐H, Random, 95% CI)	1.51 [0.68, 3.34]
5.2 DTPw ‐ immunogenicity failure	10	3574	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.43, 2.16]
6 Anti‐BPT (Pertussis) Show forest plot	11	2928	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.80, 1.28]

6.1 DTPa ‐ immunogenicity failure	2	479	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.75, 1.25]
6.2 DTPw ‐ immunogenicity failure	9	2449	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.69, 2.57]
7 Anti‐D (Diphtheria) Show forest plot	17	4560	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.59, 1.38]

7.1 DTPa ‐ immunogenicity failure	9	2172	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.73, 1.14]
7.2 DTPw ‐ immunogenicity failure	8	2388	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.39, 1.91]
8 Anti‐T (Tetanus) Show forest plot	18	4644	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.04, 8.95]

8.1 DTPa ‐ immunogenicity failure	9	2173	Risk Ratio (M‐H, Random, 95% CI)	2.22 [1.21, 4.06]
8.2 DTPw ‐ immunogenicity failure	9	2471	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.00, 9.94]
9 DTPa Anti‐polio type 1 below the assay cut‐off 1:8 IU/mL Show forest plot	5	1236	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.20, 7.56]

10 DTPa Anti‐polio type 2 below the assay cut‐off 1:8 IU/mL Show forest plot	5	1228	Risk Ratio (M‐H, Random, 95% CI)	1.84 [0.66, 5.12]

11 DTPa Anti‐polio type 3 below the assay cut‐off 1:8 IU/mL Show forest plot	5	1233	Risk Ratio (M‐H, Random, 95% CI)	1.87 [0.59, 5.94]

12 Serious adverse events Show forest plot	9	5232	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.58, 1.53]

12.1 DTPa	3	1298	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.41, 1.37]
12.2 DTPw	6	3934	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.64, 3.13]
13 Pain Show forest plot	18	19745	Risk Ratio (M‐H, Random, 95% CI)	1.09 [1.02, 1.16]

13.1 DTPa	8	10516	Risk Ratio (M‐H, Random, 95% CI)	1.20 [1.08, 1.34]
13.2 DTPw	10	9229	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.98, 1.11]
14 Redness Show forest plot	18	19745	Risk Ratio (M‐H, Random, 95% CI)	1.09 [1.01, 1.18]

14.1 DTPa	8	10516	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.98, 1.27]
14.2 DTPw	10	9229	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.96, 1.17]
15 Swelling Show forest plot	18	19745	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.98, 1.11]

15.1 DTPa	8	10516	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.95, 1.18]
15.2 DTPw	10	9229	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.95, 1.12]
16 Fever Show forest plot	14	17805	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.96, 1.09]

16.1 DTPa	7	9811	Risk Ratio (M‐H, Random, 95% CI)	1.11 [1.00, 1.24]
16.2 DTPw	7	7994	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.92, 1.04]
17 Fussiness or restlessness Show forest plot	9	12183	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.95, 1.09]

17.1 DTPa	7	9811	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.92, 1.11]
17.2 DTPw	2	2372	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.90, 1.23]
18 Drowsiness Show forest plot	11	12011	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.89, 1.09]

18.1 DTPa	6	6830	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.88, 1.19]
18.2 DTPw	5	5181	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.82, 1.01]
19 Irritability or tenderness Show forest plot	9	8273	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.91, 1.04]

19.1 DTPa	2	1761	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.74, 1.44]
19.2 DTPw	7	6512	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.90, 1.01]
20 Poor appetite Show forest plot	11	13922	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.94, 1.08]

20.1 DTPa	6	9229	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.94, 1.18]
20.2 DTPw	5	4693	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.89, 1.06]
21 Vomiting Show forest plot	7	8281	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.90, 1.23]

21.1 DTPa	4	7262	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.89, 1.23]
21.2 DTPw	3	1019	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.64, 1.81]
22 Diarrhoea Show forest plot	6	5761	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.94, 1.32]

22.1 DTPa	3	4742	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.93, 1.34]
22.2 DTPw	3	1019	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.69, 1.77]
23 Unusual crying Show forest plot	6	5890	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.49, 1.05]

23.1 DTPa	2	3591	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.27, 7.84]
23.2 DTPw	4	2299	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.37, 1.10]
24 Sleeping more than usual Show forest plot	4	6563	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.89, 1.11]

24.1 DTPa	4	6563	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.89, 1.11]

Comparison 1. DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines

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