Methods

Site: Ghana
Design: parallel‐group RCT

Participants

Included: age 6 weeks
Excluded: neurological disorder; serious disease; birth weight < 2 kg

Interventions

Primary series

(aP versus wP)

1. DTaP: Biken[2] liquid

2. DTaP: Biken[2] freeze dried

3. DTwP: Connaught[W]

Number randomised: 266 aP, 137 wP
Dose schedule: 3 doses (6, 10, 14 weeks)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: excluded (no laboratory confirmation of pertussis cases)

2. Primary series non‐completion (due to adverse events): no data

3. Deaths: until 12 months after 3rd dose (16 months after 1st dose)

4. Encephalopathy: no data

5. Convulsions: within 7 days of any dose

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: drowsiness, fever, prolonged crying, vomiting within 7 days of each dose

Notes

Local adverse events excluded (results only for all local adverse event types combined). No statement on antipyretic/analgesic use. In this review, results are combined for the 2 aP vaccine formulations

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Using a computer program (EPI Info)

Allocation concealment (selection bias)

Unclear risk

On‐site computer assignment but file locking not reported. Vaccines visually distinguishable

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Parents and nurses collecting efficacy and adverse event data were blinded but blinding details not stated

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Parents and nurses collecting efficacy and adverse event data were blinded but blinding details not stated

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Parents and nurses collecting efficacy and adverse event data were blinded but blinding details not stated

Methods

Site: Sweden
Design: DB parallel‐group RCT

Active case ascertainment (monthly telephone). Case incidence adjusted for follow‐up duration by actuarial method. Parents recorded adverse events in diary

Participants

Included: age 5 to 11 months

Excluded: suspected progressive neurological disease; failure to thrive; renal failure; cardiac failure; prior pertussis or pertussis immunisation

Interventions

Primary series (aP versus placebo)

1. aP: JNIH7[1]

2. aP: JNIH6[2]

3. Placebo

Number randomised: 2837 aP, 954 placebo
Dose schedule: 2 doses (entry + 8 to 12 weeks later)
Concurrent vaccines: DT and IPV (not within 1 week before or 2 weeks after aP or wP)

Outcomes

1. Efficacy: 3801 infants randomised in a 3:3:2 ratio ‐ 1428 to JNIH7, 1419 to JNIH6, 954 to placebo. Of these, 1403, 1385 and 923 were assessed for efficacy in the 3 groups, respectively. Assessment commenced 30 days after the second dose and lasted for 17 to 19 months. Efficacy data were not available for the intention‐to‐treat population. Several case definitions, those closest to the definitions selected for review were: whooping cough = 21 days paroxysmal cough with whoops "after adjustment for non‐pertussis disease" (i.e. exclusion of cases that could not be verified by culture, serology or contact with culture‐proven case). Pertussis disease = cough for 7 days or more or household exposure to pertussis, with confirmation by appropriate serology

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until 15 to 17 months after 2nd dose (17 to 19 months after 1st dose)

4. Encephalopathy: no data

5. Convulsions: within 14 days of any dose

6. Hypotonic‐hyporesponsive episodes: within 14 days of any dose

7. Minor adverse events: anorexia, drowsiness, fever, irritability, prolonged crying, vomiting, pain/tenderness, redness, swelling/induration within 1 day of each dose

Notes

Macrolide prophylaxis not used (not recommended in Sweden for age > 6 months and efficacy follow‐up in this study started at minimum age of 7 months). Reactive antipyretic/analgesic use allowed. Blinding of study nurses confirmed by questionnaire

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centrally generated random sequence

Allocation concealment (selection bias)

Low risk

Vaccines in identical, coded vials

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: Sweden
Design: DB parallel‐group RCT

Passive case ascertainment (based on laboratory reports of pertussis and questionnaire of parents at 18‐month visit). Case incidence adjusted for follow‐up duration by Cox proportional hazard regression. Follow‐up of serious adverse events by active weekly surveillance in study area hospitals, reports from participating physicians and child health nurses, plus questioning of parents at each trial dose and when the child was 18 months old

Participants

Included: age 2 months
Excluded: progressive neurological disease; uncontrolled epilepsy; infantile spasm; failure to thrive; renal failure; cardiac failure; immunosuppression; prior pertussis

Interventions

Primary series (aP versus wP)

1. DTaP: SKB[2]

2. DTaP: Chiron‐Biocine[3]

3. DTaP: Connaught[5]

4. DTwP: Connaught[W]

Number randomised: 62172 aP, 2072 wP
Dose schedules: 3 doses (3, 5, 10 months ‐ 88% of vaccinees; 2, 4, 6 months ‐ 12% of vaccinees)
Concurrent vaccines: HiB and IPV

Outcomes

1. Efficacy: excluded (case ascertainment not active)

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until mean of 22 months after 3rd dose

4. Encephalopathy: within 2 days of any dose

5. Convulsions: within 2 days of any dose

6. Hypotonic‐hyporesponsive episodes: within 3 days of any dose

7. Minor adverse events: not studied

Notes

There was good evidence that the passive case ascertainment led to significant under‐reporting of cases. It is possible (not discussed in study report) that under‐reporting of serious adverse events may have occurred but there are no grounds to suspect that under‐reporting would affect the acellular and whole‐cell groups differently
Deaths recorded for this study are due to any cause and include at least 1 due to injury (vaccine group not specified)
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centrally generated random sequence

Allocation concealment (selection bias)

Low risk

Vaccines in identical, coded vials

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: USA

Design: DB parallel‐group RCT

Participants

Included: age 2 months; healthy
Excluded: not stated

Interventions

Primary series (aP versus wP)
1. DTaP: Wyeth/Takeda[4]
2. DTwP: Wyeth[W]
Number randomised: 19 aP, 20 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied.

2. Primary series non‐completion (due to adverse events): included

3. Deaths: no data

4. Encephalopathy: within 14 days of any dose

5. Convulsions: within 14 days of any dose

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, irritability, prolonged crying, pain/tenderness, redness, swelling/induration within 2 days of each dose

Notes

Reactive analgesic/antipyretic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central randomisation

Allocation concealment (selection bias)

Low risk

Vaccines in coded vials

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: age 4 to 6 years; healthy; completed DTwP primary series and 15‐ to 24‐month booster
Excluded: personal or family history of developmental delay or neurological disorder; previous aP or DTaP; previous contraindicating reaction to DTwP

Interventions

Booster (wP.wP.aP versus wP.wP.wP)

1. DTaP: Connaught/Biken[2]

2. DTwP: Connaught[W]

Number randomised: 240 aP, 76 wP
Dose schedule: 1 dose (4 to 6 years)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: within 14 days of dose

6. Hypotonic‐hyporesponsive episodes: within 14 days of dose

7. Minor adverse events: anorexia, drowsiness, fever, irritability, prolonged crying, pain/tenderness, redness, swelling/induration within 3 days of dose

Notes

Prophylactic antipyretic/analgesic use not allowed. Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation at study site, but details not reported

Allocation concealment (selection bias)

Unclear risk

Allocation concealment details not reported

Selective reporting (reporting bias)

High risk

Data for vomiting collected but not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Age: 15 to 20 months; healthy; completed DTwP primary series
Excluded: personal or family history of developmental delay or neurological disorder; previous DTaP; previous contraindicating reaction to DTwP

Interventions

BOOSTER (wP.aP versus wP.wP)

1. DTaP: SKB[3]

2. DTwP: Lederle[W]

Number randomised: 110 aP, 22 wP
Dose schedule: 1 dose (15 to 20 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied.

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, prolonged crying, pain/tenderness, redness, swelling/induration within 3 days of dose

Notes

Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Details not reported

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

High risk

Data for vomiting collected but not reported (stated to be "infrequent" and "not significantly different")

Methods

Site: USA
Design: parallel‐group RCT

Participants

Included: age 2 months
Excluded: not stated

Interventions

Primary series (aP versus wP)

1. DTaP: Chiron/Biocine[3]

2. DTwP: Connaught[W]

Number randomised: 2000 aP, 498 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccines: HiB (separate injection site) and OPV

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): no data

3. Deaths: data incomplete (SIDS only)

4. Encephalopathy: no data

5. Convulsions: within 2 days of any dose

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, irritability, pain/tenderness, redness, swelling/induration within 2 days of each dose

Notes

Booster dose of Chiron/Biocine[3] or Lederle/Takeda[4] at age 15 to 18 months. Data for this dose are not included as there was no DTwP or placebo control
SIDS was recorded in 4/2000 (0.2%) DTaP and 1/498 (0.2%) DTwP recipients in the first year of life. Death due to other causes was not studied
Late onset fever (> 3 days after dose) occurred in both groups, with peak percentage slightly higher in DTaP group (approximately 5% versus 4.5% in DTwP group) but the overall percentage with fever over the 14‐day follow‐up was lower in the DTaP group
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Details not reported

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: Sweden
Design: parallel‐group RCT

Participants

Included: age 6 months
Excluded: contraindication to DTP vaccine as per ref Anon 1977

Interventions

Primary series (aP versus wP ‐ see notes)

1. aP: JNIH6[2]

2. wP: Wellcome[W]

3. Placebo ‐ see notes

Number randomised: 121 aP, 119 P, 79 wP
Dose schedule: 3 doses (6, 7, 8 months)
Concurrent vaccine: DT and polio vaccines not given within 2 weeks of dose

Outcomes

1. Efficacy: excluded (no data on number of cases in DTwP group)

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until 1 month after 3rd dose (5 months after 1st dose)

4. Encephalopathy: until at least 1 week after 3rd dose (4 months after 1st dose)

5. Convulsions: until at least 1 week after 3rd dose (4 months after 1st dose)

6. Hypotonic‐hyporesponsive episodes: until at least 1 week after 3rd dose (4 months after 1st dose)

7. Minor adverse events: drowsiness, fever, irritability, redness, swelling/induration within 1 day of dose

Notes

The whole‐cell series was given as 3 doses of whole‐cell vaccine.
The acellular series was given as 3 doses of acellular vaccine, or 2 doses of acellular vaccine plus 1 dose of placebo (replacing the 1st, 2nd or 3rd dose of acellular vaccine). In this review, data for series non‐completion, deaths and serious adverse events relate to all acellular‐containing vaccine regimens. The acellular primary series non‐completion (due to adverse events) data include 1 infant who withdrew after receiving placebo at the 1st dose. Data for minor adverse events at each dose are recorded only for those patients who actually received the acellular vaccine at that dose
Data for anorexia and vomiting collected but not reported
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random sequence key concealed from study personnel and parents

Allocation concealment (selection bias)

Low risk

Vaccines indistinguishable

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Selective reporting (reporting bias)

High risk

Data for anorexia and vomiting collected but not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 17 to 24 months; healthy; completed DTwP primary series
Excluded: not stated

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: Lederle/Takeda[4]

2. DTwP: Lederle[W]

Number randomised: 38 aP, 37 wP
Dose schedule: 1 dose (17 to 24 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, vomiting, pain/tenderness, redness, swelling/induration within 2 days of dose

Notes

Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Details not reported

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 2 months; healthy
Excluded: not stated

Interventions

Primary series (aP versus wP)

1. DTaP: Lederle/Takeda[4]

2. DTwP: Lederle/Takeda[W]

Number randomised: 245 aP, 252 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until 12 months after 3rd dose (16 months after 1st dose)

4. Encephalopathy: no data

5. Convulsions: within 3 days of any dose

6. Hypotonic‐hyporesponsive episodes: within 3 days of any dose

7. Minor adverse events: drowsiness, fever, irritability, prolonged crying, vomiting, pain/tenderness, redness, swelling/induration within 3 days of each dose

Notes

1 death in DTwP arm due to accident (strangulation by pacifier cord)
4th dose of DTaP given at 18 months to all children. 4th dose not included in review because no DTwP control group for that dose.
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Phased parallel‐group RCT (2 to 3 vaccines per phase)

Parents recorded adverse events on forms

Participants

Included: age 6 to 12 weeks; healthy
Excluded: born < 36 weeks gestation; immune system disease; major congenital malformation; serious chronic disease; developmental delay; neurological disease; convulsions; other contraindications to DTP vaccine as per ref CID 1991a

Interventions

Primary series (aP versus wP)

1. DTaP: Biocine[1]

2. DTaP: SSVI[1]

3. DTaP: Connaught/Biken[2]

4. DTaP: Michigan[2]

5. DTaP: Pasteur‐Merieux[2]

6. DTaP: SKB[2]

7. DTaP: Biocine[3]

8. DTaP: Lederle[3]

9. DTaP: SKB[3P]

10. DTaP: Connaught[4]

11. DTaP: Porton[4]

12. DTaP: Lederle/Takeda[4]

13. DTaP: Connaught[5]

14. DTwP: Lederle[W]

Number randomised: 1827 aP, 373 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: HiB

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until 1 month after 3rd dose (5 months after 1st dose)

4. Encephalopathy: until 1 month after 3rd dose

5. Convulsions: until 1 month after 3rd dose

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, pain/tenderness, redness, swelling/induration within 3 days of each dose

Notes

In this review, safety results are combined for all acellular vaccines. Irritability and pain were reported only for the moderate/severe category
At an additional retrospective medical record review 1 year after dose 3 (not all subjects studied), convulsions were documented in 1.1% DTaP recipients compared to 0.7% DTwP
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Vaccine vials labelled with letter codes instead of type/manufacturer details but unable to ascertain from study report whether vaccinators remained unaware of what each code represented

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Vaccinators took no further part in the study and did not participate in follow‐up data collection, so outcome assessment was double‐blind

Methods

Site: USA

Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: age 18 to 24 months; completed DTwP primary series
Excluded: not stated

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: Wyeth/Takeda[4]

2. DTwP: Wyeth[W]

Number randomised: 20 aP, 20 wP
Dose schedule: 1 dose (18 to 24 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: within 1 month of dose

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, irritability, pain/tenderness, redness, swelling/induration within 1 day of dose

Notes

No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

High risk

Data for drowsiness and vomiting collected but not reported (stated to be "rare"). Data for irritability, pain, redness and induration only reported for moderate/severe category

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: age 4 to 6 years; completed DTwP primary series and 15‐ to 24‐month booster
Excluded: not stated

Interventions

Booster (wP.wP.aP versus wP.wP.wP)

1. DTaP: Wyeth/Takeda[4]

2. DTwP: Wyeth[W]

Number randomised: 20 aP, 20 wP
Dose schedule: 1 dose (4 to 6 years)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: within 1 month of dose

5. Convulsions: within 1 month of dose

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, irritability, pain/tenderness, redness, swelling/induration within 1 day of dose

Notes

No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

High risk

Data for drowsiness and vomiting collected but not reported (stated to be "rare’'). Data for irritability, pain, redness and induration only reported for moderate/severe category

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: infants
Excluded: previous DTP vaccination

Interventions

Primary series (aP versus wP)

1. DTaP: Merieux[2]

2. DTwP: Connaught[W]

Number randomised: 23 aP, 27 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until at least 2 weeks after 3rd dose (4 months after 1st dose)

4. Encephalopathy: until at least 2 weeks after 3rd dose (4 months after 1st dose)

5. Convulsions: until at least 2 weeks after 3rd dose (4 months after 1st dose)

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, fever, irritability, pain/tenderness within 3 days of dose; redness, swelling/induration within 1 day of dose

Notes

Follow‐up for deaths probably longer than until 2 weeks after dose 3 but not clearly stated to be so
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: age 18 to 24 months; completed DTwP primary series
Excluded: not stated

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: Merieux[2]

2. DTwP: Connaught[W]

Number randomised: 19 aP, 21 wP
Dose schedule: 1 dose (18 to 24 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: until at least 2 weeks after dose

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, fever, irritability, pain/tenderness within 3 days of dose; redness, swelling/induration within 1 day of dose

Notes

No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: age 4 to 6 years; completed DTwP primary series and 18‐ to 24‐month booster
Excluded: not stated

Interventions

Booster

(wP.wP.aP versus wP.wP.wP)

1. DTaP: Merieux[2]

2. DTwP: Connaught[W]

Number randomised: 20 aP, 20 wP
Dose schedule: 1 dose (4 to 6 years)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: until at least 2 weeks after dose

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, fever, irritability, pain/tenderness within 3 days of dose; redness, swelling/induration within 1 day of dose

Notes

No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: Houston, USA
Design: parallel‐group RCT

Parents were interviewed by telephone. Parents recorded adverse events in diary for 14 days after immunisations

Participants

Included: ages 16 to 20 months, who had received primary immunisation with DTwP
Excluded: not stated

Interventions

Booster (aP versus wP)

1. DTaP: local laboratory [5]

2. DTwP: Connaught [W]

Number randomised: 28 aP, 13 wP
Dose schedule: 1 dose (16 to 20 months)
Concurrent vaccines: none

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability/fretfulness, prolong crying, vomiting, pain/tenderness, redness, swelling/induration

Notes

Prolonged crying was studied as increased crying. Use of analgesic/antipyretic was allowed during the study

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: age 16 to 21 months; healthy; completed DTwP primary series
Excluded: known immune deficiency; receipt of blood products in past month; contraindication to DTwP as specified in ref CID 1991a; physician did not recommend DTwP

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: Massachusetts[1]

2. DTaP: Biocine[1]

3. DTaP: Connaught/Biken[2]

4. DTaP: Lederle[3]

5. DTaP: Biocine[3]

6. DTaP: SKB[3]

7. DTaP: Porton[4]

8. DTaP: Wyeth/Takeda[4]

9. DTaP: Connaught[5]

10. DTwP: Connaught[W]

11. DTwP: Massachusetts[W]

12. DTwP: Lederle[W]

Number studied: 102 aP, 29 wP
Dose schedule: 1 dose (16 to 21 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: until post‐vaccination phlebotomy (timing not specified)

6. Hypotonic‐hyporesponsive episodes: until post‐vaccination phlebotomy (timing not specified)

7. Minor adverse events: fever, pain/tenderness, redness, swelling/induration within 2 days of dose

Notes

The number of 16‐ to 24‐month old children randomised to aP or wP was not stated. A total of 258 children aged 16 to 24 months or 4 to 6 years were randomised in Englund 1994a and Englund 1994b combined: 192 to aP and 66 to wP. 240 of these contributed safety data
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

High risk

Data for irritability collected but not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: age 4 to 6 years; healthy; completed DTwP primary series and 15‐ to 24‐month booster
Excluded: known immune deficiency; receipt of blood products in past month; contraindication to DTwP as specified in ref CID 1991a; physician did not recommend DTwP

Interventions

Booster (wP.wP.aP versus wP.wP.wP)

1. DTaP: Massachusetts[1]

2. DTaP: Biocine[1]

3. DTaP: Connaught/Biken[2]

4. DTaP: Lederle[3]

5. DTaP: Biocine[3]

6. DTaP: SKB[3]

7. DTaP: Porton[4]

8. DTaP: Wyeth/Takeda[4]

9. DTwP: Connaught[W]

10. DwTP: Massachusetts[W]

11. DTwP: Lederle[W]

Number studied: 80 aP, 29 wP
Dose schedule: 1 dose (16 to 21 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: until post‐vaccination phlebotomy (timing not specified)

6. Hypotonic‐hyporesponsive episodes: until post‐vaccination phlebotomy (timing not specified)

7. Minor adverse events: fever, pain/tenderness, redness, swelling/induration within 2 days of dose

Notes

Number of 4 to 6‐year old children randomised to aP or wP not stated. A total of 258 children aged 16 to 24 months or 4 to 6 years were randomised in Englund 1994a and Englund 1994b combined: 192 to aP and 66 to wP. 240 of these contributed safety data.
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

Low risk

Data for irritability collected but not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 15 to 24 months; healthy; completed DTwP primary series
Excluded: immune dysfunction; major congenital malformation; serious chronic disorder; developmental delay; receipt of immunoglobulin within past 3 months

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: Connaught/Biken[2]

2. DTwP: Connaught[W]

Number randomised: 84 aP, 78 wP
Dose schedule: 1 dose (15 to 24 months)
Concurrent vaccine: OPV; HiB 4 weeks after study vaccine

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: within 3 days of dose

6. Hypotonic‐hyporesponsive episodes: within 3 days of dose

7. Minor adverse events: anorexia, drowsiness, fever, irritability, pain/tenderness, redness, swelling/induration within 1 day of dose; prolonged crying within 3 days of dose

Notes

Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

High risk

Data for vomiting collected but not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 2 months; healthy
Excluded: born < 36 weeks gestation; immune disorder; major congenital malformation; serious chronic disease; ongoing immunoglobulin therapy; pertussis infection; personal or family history of neurological disorder or developmental delay

Interventions

Primary series (aP versus wP)

1. DTaP: Connaught/Biken[2]

2. DTwP: Connaught[W]

Number randomised: 109 aP, 36 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: OPV

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded ‐ see notes

3. Deaths: until at least 14 days after 3rd dose (4 months after 1st dose)

4. Encephalopathy: until age 12 months (10 months after 1st dose)

5. Convulsions: within 14 days of any dose

6. Hypotonic‐hyporesponsive episodes: within 14 days of any dose

7. Minor adverse events: excluded (separate data for each dose not available)

Notes

1 infant did not complete the primary series due to an adverse event (high pitched cry) but the report does not state whether this infant received aP or wP. Deaths were not specifically reported but all infants either completed the study up to the final dose or withdrew due to reasons other than death
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

High risk

Data for vomiting collected but not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 17 to 24 months; healthy; full‐term; completed DTwP primary series
Excluded: acute or chronic illness; history of diphtheria, tetanus or pertussis; known contraindication to DTP

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: Lederle/Takeda[4] (lot 1)

2. DTaP: Lederle/Takeda[4] (lot 2)

3. DTaP: Lederle/Takeda[4] (lot 3)

4. DTwP: Lederle[W]

Number randomised: 345 aP, 52 wP
Dose schedule: 1 dose (17 to 24 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: within 10 days of dose

6. Hypotonic‐hyporesponsive episodes: within 10 days of dose

7. Minor adverse events: drowsiness, fever, irritability, vomiting, pain/tenderness, redness, swelling/induration within 3 days of dose

Notes

Results for DTaP lots combined
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

On‐site randomisation

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

High risk

Data for prolonged crying collected but not reported

Methods

Site: Italy

Design: DB parallel‐group RCT
Passive and active case ascertainment (parent report and monthly telephone). Case incidence adjusted for follow‐up duration by use of incidence density. Parents recorded adverse events in diary

Participants

Included: age 6 to 12 weeks; weight > 3rd percentile
Excluded: history of seizures or central nervous system disease; known/suspected immunological deficit; major congenital abnormality; failure to thrive; renal failure; prior pertussis or pertussis vaccination

Interventions

Primary series (aP versus wP versus DT)

1. DTaP: SKB[3]

2. DTaP: Biocine[3]

3. DTwP: Connaught[W]

4. DT

Number randomised: 9368 aP, 4678 wP, 1555 DT
Dose schedule: 3 doses (6 to 12, 13 to 20, and 21 to 28 weeks)
Concurrent vaccine: OPV and hepatitis B vaccine with doses 1 and 2. Booster dose of DT to all subjects at 12 months of age

Outcomes

1. Efficacy: 15,601 infants randomised and received at least 1 dose of vaccine: 4696 SKB, 4672 Biocine, 4678 DTwP and 1555 DT (randomisation ratio 3:3:3:1). Main efficacy assessment was in children who had received all 3 doses of study vaccine, commenced 30 days after 3rd dose and lasted 17 months. It included 4481 SKB, 4452 Biocine, 4358 DTwP and 1470 DT subjects. Efficacy data were also available for the intent‐to‐treat population. Several case definitions used. Those closest to the definitions selected for review were: whooping cough = 21 days or more of paroxysmal cough with confirmation by culture or appropriate serology. Pertussis disease = 7 days or more of paroxysmal cough with confirmation by culture or appropriate serology

2. Primary series non‐completion (due to adverse events): included

3. Deaths: within 60 days of any dose (6 months after 1st dose)

4. Encephalopathy: within 60 days of any dose (6 months after 1st dose)

5. Convulsions: within 60 days of any dose (6 months after 1st dose)

6. Hypotonic‐hyporesponsive episodes: within 2 days of each dose

7. Minor adverse events: excluded (separate data for each dose not available)

Notes

No statement on macrolide prophylaxis. Possible partial unblinding of DTwP (not discussed in article but study used same DTwP as Gustafsson96)
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Details not reported

Allocation concealment (selection bias)

Low risk

Vaccines in identical, coded vials

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: Sweden
Design: DB parallel‐group RCT

Passive and active case ascertainment (parent report and telephone every 6 to 8 weeks). Case incidence adjusted for follow‐up duration by use of Cox proportional hazards regression. Parents recorded adverse events in diary

Participants

Included: age 2 to 3 months
Excluded: progressive neurological disease; failure to thrive; renal failure; cardiac failure; uncontrolled epilepsy; infantile spasms; immunosuppression; prior pertussis or pertussis vaccination

Interventions

Primary series (aP versus wP versus DT)

1. DTaP: SKB[2]

2. DTaP: Connaught[5]

3. DTwP: Connaught[W]

4. DT

Number randomised: 5153 aP, 2102 wP, 2574 DT
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: inactivated polio vaccine and HiB at least 2 weeks after study vaccine

Outcomes

1. Efficacy: 9829 infants randomised and received at least 1 dose of vaccine: 2566 SKB, 2587 Connaught DTaP, 2102 DTwP and 2574 DT. Due to delayed availability of the DTwP, children were randomised only to DTaP and DT vaccines during the first 2 months of the trial. Main efficacy assessment was in children who had received all 3 doses of study vaccine, commenced 30 days after the 3rd dose and lasted for 21 months. It included 2538 SKB, 2551 Connaught DTaP, 2001 DTwP and 2538 DT subjects. Efficacy data were also available for the intention‐to‐treat population. Comparisons between DTaP and DT vaccines utilised data from all children randomised to those vaccines over the whole trial period. Comparisons involving the whole‐cell vaccine utilised data only from children who were enrolled after the date the whole‐cell vaccine became available. Several case definitions used. Those closest to the definitions selected for review were: whooping cough = 21 days or more of paroxysmal cough with confirmation by culture, appropriate serology or documented household contact with a culture‐confirmed case. Pertussis disease = more than 7 days of cough with confirmation as above

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until 2 years after 3rd dose (28 months after 1st dose)

4. Encephalopathy: within 60 days of any dose (6 months after 1st dose)

5. Convulsions: within 60 days of any dose (6 months after 1st dose)

6. Hypotonic‐hyporesponsive episodes: within 60 days of any dose (6 months after 1st dose)

7. Minor adverse events: fever, prolonged crying, redness, swelling/induration, pain/tenderness within 1 day of dose

Notes

Macrolide prophylaxis not used (not recommended in Sweden for age > 6 months and main efficacy follow‐up in this study started at age 6 months)
DTwP unavailable for first 2 months of study. Only DTaP and DT randomised during that period. Questionnaire of study nurses showed partial post‐allocation unblinding of DTwP (harder to re‐suspend and more likely to be followed by adverse events). Pre‐allocation concealment was determined to be adequate (see text for reasons)
Redness reported only for moderate/severe category
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centrally generated randomisation in blocks of 12 or 16

Allocation concealment (selection bias)

Low risk

Vaccines in identical vials. At each study site, vaccines administered in numbered order

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: Canada
Design: DB parallel‐group RCT

Adverse events recorded by structured telephone interview of parents

Participants

Included: age 2 months; healthy
Excluded: children with contraindications to pertussis vaccine as specified in ref NACI 1989

Interventions

Primary series (aP versus wP)

1. DTaP: Connaught[5]

2. DTaP: Connaught[5]

3. DTaP: Connaught[W]

Number randomised: 67 aP, 33 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: HiB

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until 1 month after 3rd dose (5 months after 1st dose)

4. Encephalopathy: no data

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, vomiting, pain/tenderness, redness, swelling/induration within 2 days of each dose

Notes

The 2 acellular vaccines had differing amounts of PT and FH. In this review, results for the 2 acellular vaccine formulations are combined

Antipyretic/analgesic prophylaxis was discouraged but not prohibited

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation list kept in a locked file

Allocation concealment (selection bias)

Low risk

Vaccines in identical, coded vials

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: Canada
Design: DB parallel‐group RCT

Adverse events recorded by structured telephone interview of parents

Participants

Included: age 17 to 19 months; healthy
Excluded: children with contraindications to pertussis vaccine as specified in ref NACI 1989

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: Connaught[5]

2. DTaP: Connaught[5]

3. DTwP: Connaught[W]

Number randomised: 61 aP, 30 wP
Dose schedule: 1 dose (17 to 19 months)
Concurrent vaccine: Hib

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, vomiting, pain/tenderness, redness, swelling/induration within 2 days of dose

Notes

The 2 acellular vaccines had differing amounts of PT, FH, Prn and Fim2,3. In this review, results for the 2 acellular vaccine formulations are combined
Antipyretic/analgesic prophylaxis was discouraged but not prohibited

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation list kept in a locked file

Allocation concealment (selection bias)

Low risk

Vaccines in identical, coded vials

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: Canada
Design: DB parallel‐group RCT. Subjects had been randomised and received primary series in Halperin 1994a

Adverse events recorded by structured telephone interview of parents

Participants

Included: age 17 to 19 months; healthy; primary series DTaP or DTwP given in Halperin 1994a
Excluded: children with contraindications to pertussis vaccine as specified in ref NACI 1989

Interventions

Booster (aP.aP versus wP.wP)

1. DTaP: Connaught[5]

2. DTaP: Connaught[5]

3. DTwP: Connaught[W]

Number studied: 56 aP, 30 wP
Dose schedule: 1 dose (17 to 19 months)
Concurrent vaccine: Hib

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: within 2 days of dose

6. Hypotonic‐hyporesponsive episodes: within 2 days of dose

7. Minor adverse events: anorexia, fever, irritability, vomiting, pain/tenderness, redness, swelling/induration within 2 days of dose

Notes

The 2 acellular vaccines had differing amounts of PT and FH. In this review, results for the 2 acellular vaccine formulations are combined. DTaP or DTwP primary series was given in Halperin 1994a. Randomisation took place in that study, parents and investigators remained blinded and children received the same vaccine in Halperin 1995 as they had received in Halperin 1994a
Antipyretic/analgesic prophylaxis was discouraged but not prohibited

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation list kept in a locked file

Allocation concealment (selection bias)

Low risk

Vaccines in identical, coded vials

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: Canada
Design: DB parallel‐group RCT

Adverse events recorded by structured telephone interview of parents

Participants

Included: age 2 to 3 months; healthy
Excluded: children with contraindications to pertussis vaccine

Interventions

Primary series + booster (aP.aP versus wP.wP)

1. DTaP: Connaught[5]

2. DTwP: Connaught[W]

Number randomised: 324 aP, 108 wP
4 doses (2, 4, 6, 17 to 19 months)
Concurrent vaccine: Hib

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): included

3. Deaths: included up to 3rd dose (4 months after 1st dose). Excessive loss to follow‐up after that dose

4. Encephalopathy: no data

5. Convulsions: until 1 to 2 months after 3rd dose

6. Hypotonic‐hyporesponsive episodes: until 1 to 2 months after 3rd dose

7. Minor adverse events: anorexia, drowsiness, fever, irritability, prolonged crying, pain/tenderness, redness, swelling/induration within 2 days of each dose

Notes

Antipyretic/analgesic prophylaxis was discouraged but not prohibited

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation list kept in a locked file

Allocation concealment (selection bias)

Low risk

Vaccines in identical, coded vials

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: Canada
Design: DB parallel‐group RCT

Adverse events recorded by structured telephone interview of parents

Participants

Included: age 4 to 6 years; healthy; primary series DTaP or DTwP given in Halperin 1994 or Halperin 1996
Excluded: children with contraindications to pertussis vaccine as specified in ref NACI 1989

Interventions

Booster (aP versus wP)

1. 5 doses DTaP‐IPV: Connaught[5]

2. 4 doses DTwP‐IPV + 1 dose DTaP‐IPV: Connaught[5]

3. 4 doses DTaP‐IPV+ 1 dose DTwP: Connaught[W]

4. 5 doses DTwP‐IPV: Connaught[W]

Number studied: 178 aP, 178 wP
Dose schedule: 1 dose (4 to 6 years)
Concurrent vaccine: IPV

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: excluded (booster)

6. Hypotonic‐hyporesponsive episodes: excluded (booster)

7. Minor adverse events: anorexia, drowsiness, fever, irritability, vomiting, pain/tenderness, redness, swelling/induration

Notes

Antipyretic/analgesic prophylaxis was discouraged but not prohibited

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation list kept in a locked file

Allocation concealment (selection bias)

Low risk

Vaccines in identical, coded vials

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: Canada
Design: parallel‐group RCT

Computer‐generated randomisation list kept in a locked file. Study personnel collecting telephone reactogenicity data were blinded as to which vaccine the subject had received

Participants

Included: age 4 to 6 years; healthy
Excluded: children with contraindications to pertussis vaccine

Interventions

Booster (aP versus wP) 

1. 4 doses DTaP‐Hib+DTaP‐IPV: Pasteur [5]  

2. 4 doses DTwP‐Hib+DTaP‐IPV: Pasteur [5] 

3. 4 doses DTwP+DTwP‐IPV: Pasteur [W]                                           

Number randomised: 408 aP, 97 wP
1 dose (4 to 6 years)

Concurrent vaccines: Hib; IPV

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, prolonged crying, pain/tenderness, redness, swelling/induration within 2 days of each dose

Notes

Only participants who had received 4 previous doses of DTwP were blinded to which vaccine they received for the fifth dose, because of different vaccine container formats. Antipyretic/analgesic prophylaxis was discouraged but not prohibited

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation list kept in a locked file

Allocation concealment (selection bias)

High risk

Different vaccine container formats

Blinding (performance bias and detection bias)
All outcomes

High risk

Study personnel collecting telephone reactogenicity data were blinded as to which vaccine the subject had received. Only participants who had received 4 previous doses of DTwP were blinded to which vaccine they received for the fifth dose

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Only participants who had received 4 previous doses of DTwP were blinded to which vaccine they received for the fifth dose

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Only participants who had received 4 previous doses of DTwP were blinded to which vaccine they received for the fifth dose

Methods

Site: Germany
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 2 to 4 months; healthy
Excluded: not stated

Interventions

Primary series (aP versus wP)

1. DTaP: Lederle/Takeda[4]

2. DTwP: Lederle[W]

Number randomised: 75 aP, 74 wP
Dose schedule: 3 doses (2 to 4 months, then 2 doses at 6‐week intervals)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): no data

3. Deaths: no data

4. Encephalopathy: no data

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, prolonged crying, redness, swelling/induration within 2 days of each dose

Notes

Excluded for adverse events after 2nd and 3rd doses (number vaccinated/studied at these doses was uncertain due to inconsistencies in tabulated data). Redness and induration were reported only for the moderate/severe category
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: Turkey
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 15 to 20 months; completed DTwP primary series
Excluded: history of pertussis or progressive neurological disease; chronic drug therapy

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: SKB[3]

2. DTwP: Behringwerke[W]

Number randomised: 55 aP, 55 wP
Dose schedule: 1 dose (15 to 20 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, pain/tenderness, redness, swelling/induration within 3 days of dose

Notes

Data for drowsiness, irritability (restlessness), "unusual" crying and "gastrointestinal symptoms" collected but not reported. Report states "no serious events" but serious events not defined
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: Turkey
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 4 to 6 years; completed DTwP primary series and 15‐ to 24‐month booster
Excluded: history of pertussis or progressive neurological disease; chronic drug therapy

Interventions

Booster (wP.wP.aP versus wP.wP.wP)

1. DTaP: SKB[3]

2. DTwP: Behringwerke[W]

Number studied: 53 aP, 52 wP
Dose schedule: 1 dose (4 to 6 years)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, pain/tenderness, redness, swelling/induration within 3 days of dose

Notes

Total 108 randomised, data for 105
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

High risk

Data for drowsiness, irritability (restlessness), "unusual" crying and "gastrointestinal symptoms" collected but not reported

Methods

Site: Thailand
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 4 to 6 years old; healthy, who had received 4 doses of DTwP at 2, 4, 6 and 18 months
Excluded: history of diphtheria or tetanus at any time, confirmed pertussis in the previous 5 years, if received vaccines not foreseen in the protocol within 30 days prior to study start or after receiving a study vaccine, history of allergic disease or reactions by any component of the vaccine or previously recorded following previous DTP, history of any serious adverse reactions following previous DTP vaccination, history of administration of immunosuppressive agents, immunoglobulin or blood products within the previous 3 months or during the trial, major congenital defects, neurological including seizure disorders and acute febrile illness

Interventions

Booster (aP versus wP)

1. DTaP: GSK [3]

2. DTwP: GSK [W]

Number studied: 165 aP, 165 wP
Dose schedule: 1 dose (4 to 6 years)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, pain/tenderness, redness, swelling/induration

Notes

All symptoms (solicited or unsolicited) were classified by the investigators as not related, unlikely, suspected or probably related. But not a clear temporal definition of this criterion (before or after data collection)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 18 to 24 months; healthy; completed DTwP primary series
Excluded: contraindication to DTwP as specified in ref CID 1982 or in the Wyeth [W] pack insert

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: Wyeth/Takeda[4]

2. DTwP: Wyeth[W]

Number randomised: 40 aP, 20 wP
Dose schedule: 1 dose (18 to 24 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, prolonged crying, vomiting, pain/tenderness, redness, swelling/induration within 2 days of dose

Notes

Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 15 to 20 months; completed DTwP primary series
Excluded: routine contraindications to DTP vaccine; immunodeficiency; immunosuppressive therapy; major congenital malformation; serious chronic disease; personal or immediate family history of developmental delay or neurological disorder; antibiotic therapy within 7 days before enrolment

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: Connaught/Biken[2]

2. DTwP: Connaught[W]

Number randomised: 164 aP, 82 wP
Dose schedule: 1 dose (15 to 20 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, prolonged crying, pain/tenderness, redness, swelling/induration at 1 day after dose

Notes

Study report states that only adverse events for which there was a significant difference between vaccines were reported. Not clear whether adverse event types were omitted or just certain time points for individual adverse events
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation but no statement regarding file locking

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

Low risk

Vomiting is the only target adverse event without data. Redness reported only for moderate/severe category

Methods

Site: UK

Design: parallel‐group RCT

Parents and study nurses recorded adverse events on forms

Participants

Included: infants attending clinics for 1st dose DTP (due at age 3 months)
Excluded: history of neurological disorder, serious chronic disease or confirmed pertussis; immediate family history of idiopathic epilepsy

Interventions

Primary series (aP versus wP)

1. DTaP: CAMR[4]

2. DTwP: Wellcome[W]

Number randomised: 94 aP, 94 wP
Dose schedule: 3 doses (3, 5, 8 to 10 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until 3rd dose (5 to 7 months after 1st dose)

4. Encephalopathy: no data

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever within 1 day of each dose

Notes

Minor adverse event data for fever only. Anorexia, drowsiness, irritability, prolonged crying and vomiting combined as "any systemic symptom"
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random sequence

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

High risk

Data for redness, swelling collected but not reported (stated not to differ in frequency)

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 4 to 6 years; healthy; completed DTwP primary series and 15‐ to 24‐month booster
Excluded: not stated

Interventions

Booster (wP.wP.aP versus wP.wP.wP)

1. DTaP: Lederle/Takeda[4]

2. DTwP: Lederle[W]

Number randomised: 41 aP, 42 wP
Dose schedule: 1 dose (4 to 6 years)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, vomiting, pain/tenderness, redness, swelling/induration within 2 days of dose

Notes

No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on questionnaires and measured their child's rectal temperature

Participants

Included: infants due to receive 1st dose DTP (mean age = 2 months), 2nd dose (mean age = 4 months) and 3rd dose (mean age = 6 months)
Excluded: contraindication to DTP vaccine as specified in ref CID 1988

Interventions

Primary series (aP versus wP)

1. DTaP: Biken/Connaught [2]

2. DTwP: Connaught [W]

Number randomised:                                                                                              

• 1 dose: 218 aP versus 72 wP

• 2 dose: 207 aP versus 62 wP 

• 3 dose: 204 aP versus 57 wP                                                 

Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): no data

3. Deaths: no data

4. Encephalopathy: no data

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, prolong crying, vomiting, pain/tenderness, redness, swelling/induration, within 2 days of each dose

Notes

The pattern of crying is not clear, considered unusual, or high‐pitched cries. 7 children left the study for severe reactions not described and 2 experienced hypotonic/hyporesponsive episodes following the second vaccination. Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: infants due to receive 1st dose DTP (mean age = 2 months)
Excluded: contraindication to DTP vaccine as specified in ref CID 1988

Interventions

Primary series (aP versus wP)

1. DTaP: SKB[2]

2. DTwP: Lederle[W]

Number randomised: 88 aP, 22 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until 3rd dose (4 months after 1st dose)

4. Encephalopathy: no data

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, irritability, pain/tenderness, redness, swelling/induration within 2 days of each dose

Notes

The choice of reported adverse event types was not limited to those showing a significant difference between vaccines but was based on the preliminary results of Decker 1995 (reported in Pichichero 1995), which identified the chosen adverse events as sufficient to differentiate between DTP vaccines in regard to reactogenicity. Irritability and pain were reported only for the moderate/severe category.

Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Selective reporting (reporting bias)

High risk

Data on anorexia, drowsiness and vomiting were collected but not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: age 2 months (6 to 12 weeks); healthy
Excluded: contraindication to DTP vaccine as specified in ref CID 1988

Interventions

Primary series (aP versus wP)

1. DTaP: SKB[3]

2. DTwP: Lederle[W]

Number randomised: 62 aP, 18 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): no data

3. Deaths: no data

4. Encephalopathy: no data

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, irritability, pain/tenderness, redness, swelling/induration, within 2 days of each dose

Notes

Redness and pain were reported only for the moderate/severe category
Antipyretic/analgesic use discouraged but allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Blinding (performance bias and detection bias)
All outcomes

Low risk

Parents and investigators are unaware of the type of vaccination

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Methods

Site: USA
Design: parallel‐group RCT. Subjects had been randomised and received primary series in Pichichero 1993 and Pichichero 1994 (latter excluded due to discrepancies in reported data). 158 out of 190 (83%) parents elected to remain blinded and allow child to participate in booster study

Parents recorded adverse events on forms

Participants

Included: age 15 to 20 months; primary series DTaP or DTwP given in Pichichero 1993 or Pichichero 1994
Excluded: not stated

Interventions

Booster (aP.aP versus wP.wP)

1. DTaP: SKB[2]

2. DTaP: SKB[3P]

3. DTwP: Lederle[W]

Number studied: 124 aP, 34 wP
Dose schedule: 1 dose (15 to 20 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, irritability, pain/tenderness, redness, swelling/induration within 3 days of dose

Notes

Possible bias due to parental self selection of 83% subset who continued in the study. Number of subjects studied for redness and pain in the DTwP group is unclear due to discrepancies in the data table. Irritability and pain were reported only for the moderate/severe category
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Design: parallel‐group RCT. Subjects had been randomised and received primary series in Decker 1995. 1374 of 2264 (61%) parents elected to remain blinded and allow child to participate in booster study

Parents recorded adverse events on forms

Participants

Included: completed DTaP or DTwP primary series in Decker 1995
Excluded: see Decker 1995; contraindications to DTP vaccine as per ref CID 1994

Interventions

Booster (aP.aP versus wP.aP versus wP.wP)

Children who had received DTaP primary series received the same DTaP as a booster, except for those who had received Lederle[3P] (no longer available) who were boosted with Lederle/Takeda[4F2]. Children who had received DTwP primary series were re‐randomised to receive 1 of the 12 DTaP vaccines or DTwP

1. DTaP: Biocine[1]

2. DTaP: SSVI[1]

3. DTaP: Connaught/Biken[2]

4. DTaP: Michigan[2]

5. DTaP: Pasteur‐Merieux[2]

6. DTaP: SKB[2]

7. DTaP: Biocine[3P]

8. DTaP: SKB[3P]

9. DTaP: Connaught[4]

10. DTaP: Porton[4]

11. DTaP: Lederle/Takeda[4]

12. DTaP: Connaught[5]

13. DTwP: Lederle[W]

Number studied: 1079 aP.aP, 187 wP.aP, 16 wP.wP
Dose schedule: 1 dose (15 to 20 months)
Concurrent vaccine: OPV

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: within 3 days of dose (possibly 2 weeks)

6. Hypotonic‐hyporesponsive episodes: within 3 days of dose (possibly 2 weeks)

7. Minor adverse events: fever, irritability, pain/tenderness, redness, swelling/induration within 3 days of dose

Notes

Most failures to proceed from primary series to booster study were due to prior receipt of booster dose or reluctance regarding venipuncture. Possible selection bias exists due to loss of 39% of subjects after primary series, although authors state that DTwP primary series recipients with severe reactions were not less likely to proceed to the booster study. Safety results are combined for all acellular vaccines. Data for drowsiness and vomiting were collected but not reported (stated to be not significantly different between groups)
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Details not reported

Allocation concealment (selection bias)

Unclear risk

Vaccine vials labelled with letter codes instead of type/manufacturer details but unable to ascertain from study report whether vaccinators remained unaware of what each code represented

Blinding (performance bias and detection bias)
All outcomes

Low risk

Vaccinators took no further part in the study and did not participate in follow‐up data collection, so outcome assessment was double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Selective reporting (reporting bias)

High risk

Data for drowsiness and vomiting were collected but not reported (stated to be not significantly different between groups)

Methods

Site: USA
Design: parallel‐group RCT. Subjects had been randomised and received primary series in Decker 1995 and Pichichero 1997. Details of allocation concealment in Decker 1995 and Pichichero 1997. Parents recorded adverse events on forms. Parents elected to remain blinded and allow child to participate in booster study

Participants

Included: age 4 to 6 years of age who had completed earlier National Institute of Allergy and Infectious Diseases (NIAID) multicentre acellular pertussis vaccine trials in Decker 1995, Pichichero 1997

Excluded: subjects with contraindications or precautions to immunisations as specified in the Report of the Committee on Infectious Diseases of the American Academy of Pediatrics

Interventions

Booster (same aPaPaP, mixed aPaPaP, wPaPaP  versus wPwPwP)

1. DTaP: Connaught/Biken[2]

2. DTaP: Connaught[2]

3. DTaP: Chiron [3]

4. DTaP: SKB[3]

5. DTaP: Connaught[4]

6. DTaP: Lederle [4]

7. DTwP: Lederle [W]

Number of studies: 316 aP, 10 wP

Dose schedule: 1 dose (4 to 6 years)

Concurrent vaccine: OPV

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, irritability, pain/tenderness, redness, swelling/induration within 3 days of dose

Notes

Possible bias due to parental self selection of 83% subset who continued in the study

Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: Italy

Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 2 months; healthy
Excluded: not stated

Interventions

Primary series (aP versus wP)

1. DTaP: Biocine[3]

2. DTwP: Biocine[W]

Number randomised: 240 aP, 240 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until 3rd dose (4 months after 1st dose)

4. Encephalopathy: until 7 days after 3rd dose

5. Convulsions: until 7 days after 3rd dose

6. Hypotonic‐hyporesponsive episodes: until 7 days after 3rd dose

7. Minor adverse events: anorexia, drowsiness, fever, irritability, vomiting, pain/tenderness, redness, swelling/induration within 2 days of each dose

Notes

No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: Germany
Design: parallel‐group RCT

Active case ascertainment (bi‐weekly telephone). Case incidence adjusted for follow‐up duration by use of incidence density. Parents recorded adverse events in diary

Participants

Included: age 2 to 4 months; healthy
Excluded: known or suspected neurological disorder, immunological dysfunction or immunosuppressive therapy; birth weight < 2 kg; significant congenital abnormality or chronic illness; history of convulsions; hereditary disease in the family with an increased risk of neurological manifestations after vaccination (for example, tuberous sclerosis); immunoglobulins in previous 4 weeks

Interventions

Primary series + booster (aP.aP versus wP.wP)

1. DTaP: Lederle/Takeda[4]

2. DTwP: Lederle[W]

A third non‐randomised group received DT (n = 1739)
Number randomised: 4273 aP, 4259 wP
Dose schedule: 4 doses (dose 1: 2 to 4 months; dose 2: at least 6 weeks after dose 1; dose 3: at least 6 weeks after dose 2 but before 1st birthday; dose 4: at least 6 months after dose 3, at 15 to 18 months of age). DT vaccinees received doses at times corresponding to doses 1, 2 and 4 of the randomised schedule
Concurrent vaccines: not stated

Outcomes

1. Efficacy: the main efficacy assessment was conducted in children who had received all 3 doses of study vaccine and commenced 2 weeks after the third dose (or at age 7 months in DT recipients). Follow‐up duration not reported but must have been at least 12 months, based on reported study dates. The number of participants in the efficacy analysis was not stated and data were not available for the intention‐to‐treat population at the time of this review. Several case definitions; that closest to a definition selected for review was: whooping cough = 21 days or more of cough with paroxysms, whoops or post‐tussive vomiting, confirmed by culture, serology or contact with a culture‐proven case). Results for other case definitions were not reported at the time of this review

2. Primary series non‐completion (due to adverse events): no data

3. Deaths: until at least 6 months after 3rd dose (12 months after 1st dose)

4. Encephalopathy: until at least 6 months after 3rd dose (12 months after 1st dose)

5. Convulsions: within 3 days of each dose

6. Hypotonic‐hyporesponsive episodes: until at least 6 months after 3rd dose (12 months after 1st dose)

7. Minor adverse events: anorexia, drowsiness, fever, irritability, prolonged crying, redness, swelling/induration within 3 days of each dose

Notes

Macrolide prophylaxis was not documented
During the total period of the study (until at least 6 months after 3rd dose) convulsions occurred in 46 (1.1%) DTaP, 56 (1.3%) DTwP and 19 (1.1%) DT recipients
Redness and induration were reported only for the moderate/severe category
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: USA
Design: parallel‐group RCT

Parents recorded adverse events on forms

Participants

Included: age 15 to 16 months; healthy; completed DTwP primary series
Excluded: past pertussis, mumps, measles or rubella; previous DTaP; contraindication to DTP, OPV or MMR vaccine

Interventions

Booster (wP.aP versus wP.wP)

1. DTaP: Lederle/Takeda[4]

2. DTwP: Lederle[W]

Number randomised: 48 aP, 49 wP
Dose schedule: 1 dose (age 15 to 16 months)
Concurrent vaccine: OPV and MMR vaccine

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): excluded (booster)

3. Deaths: excluded (booster)

4. Encephalopathy: excluded (booster)

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, fever, irritability, pain/tenderness, redness, swelling/induration within 3 days of dose

Notes

No "severe" or contraindicating adverse events but these not defined in the study report. DTaP or DTwP administered at same time as OPV and MMR (but MMR at a different injection site)
Reactive antipyretic/analgesic use allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: Senegal
Design: parallel‐group RCT

Study physicians visited homes, recorded adverse events and measured temperature at 2 to 3 days after each dose. Parents interviewed regarding deaths

Participants

Included: age 2 months
Excluded: not stated

Interventions

Primary series (aP versus wP)

1. DTaP: Pasteur‐Merieux[2]

2. DTwP: Pasteur‐Merieux[W]

Number randomised: 141 aP, 145 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: Bacille Calmette‐Guérin (BCG) (2 months); IPV (2, 4, 6 months), measles and yellow fever (6 months)

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): no data

3. Deaths: within 2 months of any dose (until 5 months after 1st dose)

4. Encephalopathy: no data

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, drowsiness, irritability, vomiting within 2 to 3 days of first dose; fever, pain/tenderness, redness, swelling/induration at 2 to 3 days after first dose

Notes

Study conducted in Senegal in an area with high background infant mortality. High loss to follow‐up (see text). Data included for 1st dose only. Second and third doses excluded because follow‐up for those doses was less than 80% in both vaccine groups. Irritability and pain were reported only for the moderate/severe category
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: Senegal
Design: parallel‐group RCT

Active case ascertainment (weekly visit by field workers). Case incidence adjusted for follow‐up duration by use of incidence density. Field workers recorded adverse events during 2 weekly visits after each dose

Participants

Included: age 2 months
Excluded: serious congenital defect; serious chronic illness manifested as failure to thrive or cardiac failure; history of seizure or neurological disorder; history of pertussis

Interventions

Primary series (aP versus wP)

1. DTaP: Pasteur‐Merieux[2]

2. DTaP: Pasteur‐Merieux[W]

Number studied (efficacy): 1847 aP, 1772 wP
Number studied (safety): 2396 aP, 2379 wP
Dose schedule: 3 doses (2, 4, 6 months)
Concurrent vaccine: BCG (2 months); IPV (2, 4, 6 months)

Outcomes

1. Efficacy: children randomised in a 1:1 ratio but the number of children receiving each vaccine was not stated. A total of 3619 were studied for efficacy (1847 DTaP and 1772 DTwP). The main efficacy assessment was conducted in children who had received all 3 doses of study vaccine, commenced 28 days after the third dose and lasted for a mean of 22 months. Efficacy data were not available for the intention‐to‐treat population. Several case definitions used. That closest to 1 of the definitions selected for review was: whooping cough = 21 days or more of paroxysmal cough with confirmation by culture or appropriate serology. Results were not reported for other case definitions at the time of review

2. Primary series non‐completion (due to adverse events): no data

3. Deaths: within 2 months of any trial dose (until 5 months after 1st dose)

4. Encephalopathy: no data

5. Convulsions: within 2 days of any dose

6. Hypotonic‐hyporesponsive episodes: within 2 days of any dose

7. Minor adverse events: not recorded systematically due to trial conditions. Available results were reported combined across 3 doses

Notes

Number randomised not stated. A total of 4821 were studied for safety.
No statement on macrolide prophylaxis
Study conducted in Senegal in an area with high background infant mortality. Deaths recorded are due to any cause and may include some due to injury. No breakdown by vaccine group of the number of deaths due to infection
A household contact substudy compared pertussis attack rates with non‐randomised unvaccinated controls
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: China
Design: parallel‐group RCT

Adverse event recording method not stated

Participants

Included: age 3 to 6 months
Excluded: not stated

Interventions

Primary series (aP versus wP versus P)

1. aP: Canton[2]

2. wP: Wuhan[W]

3. Placebo

Number studied: 105 aP, 101 wP, 100 P
Dose schedule: 3 doses at 4‐week intervals
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): no data

3. Deaths: no data

4. Encephalopathy: no data

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: fever, swelling/induration at 2 days after each dose

Notes

Number randomised not stated
Data for redness and tenderness excluded (combined as 1 outcome in study report)
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported

Methods

Site: Sweden
Design: DB parallel‐group RCT

Passive and active case ascertainment (parent report and monthly telephone). Case incidence adjusted for follow‐up duration by use of incidence density. Parents recorded adverse events in diary

Participants

Included: full‐term, healthy infants
Excluded: none stated

Interventions

Primary series (aP versus DT)

1. DTaP: Amvax[1]

2. DT

Number randomised: 1724 aP, 1726 DT
Dose schedule: 3 doses (3, 5, 12 months)
Concurrent vaccine: nil

Outcomes

1. Efficacy (median 17.5 months follow‐up after 3rd dose). Several case definitions used. Those closest to the definitions selected for review were: whooping cough = 21 days or more of paroxysmal cough with confirmation by culture, appropriate serology or household contact with a culture‐confirmed case; pertussis disease = cough for 7 days or more with confirmation as above

2. Primary series non‐completion (due to adverse events): included

3. Deaths: until (median) 17.5 months after 3rd dose

4. Encephalopathy: no data

5. Convulsions: within 7 days of any dose

6. Hypotonic‐hyporesponsive episodes: within 7 days of any dose

7. Minor adverse events: excluded. Data were reported only as percentages, rounded to nearest percent (e.g. 6%). With approximately 1700 participants in each group, numeric values could not be calculated with sufficient confidence for inclusion in the review

Notes

Macrolide prophylaxis not used (not recommended in Sweden for age > 6 months and main efficacy follow‐up in this study started at age 10 months)
Target adverse events assessed in the trial included anorexia, irritability, fever, redness and induration. Data for anorexia and irritability were collected but not reported (stated to be equally frequent with both vaccines). Data for other events are not included in the review because the number of children experiencing the event could not be determined with sufficient confidence (fever) and because data were reported only for the moderate/severe category (redness and induration)
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random sequence

Allocation concealment (selection bias)

Low risk

Vaccines indistinguishable

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Selective reporting (reporting bias)

High risk

Data for anorexia and irritability were collected but not reported (stated to be equally frequent with both vaccines)

Methods

Site: Austria and Switzerland
Design: parallel‐group RCT

Parents recorded adverse events in diary

Participants

Included: age 10 to 16 weeks; healthy
Excluded: not stated

Interventions

Primary series (aP versus wP)

1. DTaP: SKB[2]

2. DTaP: SKB[2]

3. DTwP: Behringwerke[W]

Number studied: 200 aP, 101 wP
Dose schedule: 3 doses (3, 4, 5 months)
Concurrent vaccine: not stated

Outcomes

1. Efficacy: not studied

2. Primary series non‐completion (due to adverse events): included

3. Deaths: no data

4. Encephalopathy: no data

5. Convulsions: no data

6. Hypotonic‐hyporesponsive episodes: no data

7. Minor adverse events: anorexia, fever, irritability, pain/tenderness, redness, swelling/induration within 2 days of each dose

Notes

The 2 acellular vaccine formulations contained differing amounts of PT. In this review, data for the 2 acellular vaccine formulations are combined
Total 308 enrolled but cannot determine number randomised to each vaccine. Denominator for primary series non‐completion is the number with adverse event data at the first dose (200 DTaP, 101 DTwP)
No statement on antipyretic/analgesic use

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

Details not reported