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'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 1

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

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

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

Pneumococcal conjugate vaccine compared with control intervention for preventing acute otitis media

Patient or population: children aged 12 years or younger and a follow‐up after vaccinations of at least 6 months

Settings: open population

Intervention: multivalent PCVs

Comparison: control treatment

Outcomes

VE ‐ relative effect (95% CI)*

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Frequency of all‐cause AOM

PCV7 administered in early infancy

Follow‐up 6 to 42 months

RRR: ‐5% to 7%

42,140 (4)

⊕⊕⊕⊕
high

Results are derived from 1 very large trial (Black 2000/Fireman 2003) and 3 trials of approximately equal size (944 to 1666 participants) (Eskola 2001; Kilpi 2003; O'Brien 2008)

Lowest efficacy was found in high‐risk children (O'Brien 2008)

Frequency of all‐cause AOM

PD‐PCV11 administered in early infancy

Follow‐up 27 months

RRR 34% (21 to 44)

4968 (1)

⊕⊕⊕⊝
moderate

Results derived from 1 high‐quality trial (Prymula 2006)

Part of the effect may be related to the protein D to which the polysaccharides are conjugated in the vaccine PD‐PCV11, demonstrated to reduce non‐typeable H. influenzae by 35% (95% CI 2 to 57)

AOM incidence rate in control group was low compared to the other studies on the effect on PCV7 in infants and the absolute risk difference was small (Table 1)

Frequency of all‐cause AOM

CRM197‐PCV9 administered in healthy toddlers

Follow‐up 24 months

RRR 17% (‐2 to 33)

264 (1)

⊕⊕⊕⊝
moderate

Results derived from 1 trial of moderate methodological quality (Dagan 2001). Uncertainty about the effect size (statistically non‐significant effect) and outcome measure (parent‐reported OM)

Frequency of all‐cause AOM

PCV7 administered in older children with a known history of AOM

Follow‐up 6 to 26 months

RRR ‐29% to 57%

1054 (3)

⊕⊕⊕⊕
high

Results are derived from 2 high‐quality trials (Veenhoven 2003; Van Kempen 2006) and 1 trial of moderate methodological quality (Jansen 2008). The 2 high‐quality trials found no beneficial effect of PCV in preventing AOM recurrences, while the other trial found PCV7/TIV not to be superior to TIV/placebo in preventing AOM during the influenza season

Frequency of pneumococcal AOM

PCV7 administered in early infancy

Follow‐up 6 to 42 months

RRR 20% to 34%

1233 (2)

⊕⊕⊕⊕
high

Results are derived from 2 high‐quality trials (Eskola 2001/Palmu 2009; Kilpi 2003)

Frequency of pneumococcal AOM

PD‐PCV11 administered in early infancy

Follow‐up 27 months

RRR 52% (37 to 63)

281 (1)

⊕⊕⊕⊝
moderate

Results derived from 1 high‐quality trial in which myringotomy was performed in all children (Prymula 2006)

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

*Results include both ITT and PP results; 95% CI lacking in case of multiple studies (range of effect estimates presented as we refrained from pooling).

AOM: acute otitis media
CI: confidence interval
ITT: intention‐to‐treat
OM: otitis media
PCV: pneumococcal conjugate vaccine
PP: per‐protocol
RRR: relative reduction in risk
TIV: trivalent inactivated influenza vaccine
VE: vaccine efficacy

Figures and Tables -
Table 1. The effect of pneumococcal conjugate vaccination on all‐cause acute otitis media episodes

Intention‐to‐treat

Per‐protocol

Episodes/person year

VE expressed as relative reduction in risk (95% CI)

Episodes/person year

Incidence rate difference ‐ episodes per person year (95% CI)

VE expressed as relative reduction in risk (95% CI)

Treatment

Control

Treatment

Control

PCV administered in early infancy

Black 2000

Fireman 2003

6% (4 to 9)

6% (4 to 8)

7% (4 to 10)

7% (4 to 9)

Eskola 2001

1.16

1.24

‐0.08 ˜

6% (‐4 to 16)

Kilpi 2003

‐1% (‐12 to 10)

Prymula 2006

0.08

0.13

‐0.04 ˜

34% (21 to 44)

O'Brien 2008*

1.4

1.4

‐5% (‐25 to 12)#

1.3

1.3

0.0 (‐0.13 to 0.14)

0% (‐21 to 17)

PCV administered at a later age

Dagan 2001

0.66

0.79

‐0.14 (‐0.29 to 0.02)

17% (‐2 to 33)

Veenhoven 2003

‐25% (‐57 to 1)

1.1

0.83

0.27 ˜

‐29% (‐62 to ‐2)

Van Kempen 2006

0.78

0.67

0.11 ˜

‐16% (‐96 to 31)

Jansen 2008

57% (6 to 80)^

CI: confidence interval; HBV: hepatitis B vaccine; PCV: pneumococcal conjugate vaccine; TIV: trivalent influenza vaccine; VE: vaccine efficacy.

*Cluster‐randomised trial.
#Defined as primary efficacy analysis. Analysis not entirely according to intention‐to‐treat principle as 88/944 children were not included in analysis because of not meeting strict chart review criteria.
^Index group: TIV/PCV7, control: HBV/placebo; VE TIV/placebo versus HBV/placebo: 71% (95% 30% to 88%), i.e. larger VE TIV/placebo versus HBV/placebo then TIV/PCV7 versus HBV/placebo.

˜ 95% CI could not be calculated as person‐time across treatment groups was not reported.

Note: negative values for VE expressed as relative reduction in risk represent an increase in the risk for AOM.

Figures and Tables -
Table 1. The effect of pneumococcal conjugate vaccination on all‐cause acute otitis media episodes
Table 2. The effect of pneumococcal conjugate vaccination on pneumococcal acute otitis media

Intention‐to‐treat

Per‐protocol

VE expressed as relative reduction in risk (95% CI)

VE expressed as relative reduction in risk (95% CI)

Pneumococcal

AOM

Vaccine‐type

AOM

Cross‐reactive type AOM

Non‐vaccine‐type AOM

Pneumococcal

AOM

Vaccine‐type

AOM

Cross‐reactive type AOM

Non‐vaccine‐type AOM

PCV administered in infancy

Black 2000#

Fireman 2003

65% P = 0.04

67% P = 0.08

Eskola 2001

Palmu 2009^

54% (41 to 64)

34% (21 to 45)

20% (7 to 31)

57% (44 to 67)

51% (27 to 67)

‐33% (‐80 to 1)

Kilpi 2003

25% (11 to 37)

56% (44 to 66)

‐5% (‐47 to 25)

‐27% (‐70 to 6)

Prymula 2006

52% (37 to 63)

58% (41 to 69)

66% (22 to 85)

9% (‐64 to 49)

O'Brien 2008* #

64% (‐34 to 90)

PCV administered at a later age

Dagan 2001

Veenhoven 2003

34% P = 0.22

52% P = 0.21

21% P = 0.44

Van Kempen 2006

Jansen 2008

VE: vaccine efficacy; PCV: pneumococcal conjugate vaccine; MEF: middle ear fluid.
*Cluster‐randomised trial.
#MEF collected from spontaneous draining ears; in the other studies MEF was routinely collected during AOM episodes through paracentesis.
^Additional analysis of Eskola 2001 including pneumococcal AOM by a positive culture or PCR.
Note: negative values represent an increase in the risk of AOM.

Figures and Tables -
Table 2. The effect of pneumococcal conjugate vaccination on pneumococcal acute otitis media
Table 3. The effect of pneumococcal conjugate vaccination on recurrent acute otitis media

Intention‐to‐treat

Per‐protocol

VE expressed as relative reduction in risk (95% CI)

VE expressed as relative reduction in risk (95% CI)

PCV administered in infancy

Black 2000

Fireman 2003

9% (4 to 14)

10% (7 to 13)

9% (3 to 15)

Eskola 2001

9% (‐12 to 27)

16% (‐6 to 35)

Kilpi 2003

Prymula 2006

56% (‐2 to 81)

O'Brien 2008*

PCV administered at a later age

Dagan 2001

Veenhoven 2003

Van Kempen 2006

Jansen 2008

PCV: pneumococcal conjugate vaccine; VE: vaccine efficacy.
*Cluster‐randomised trial.
Note: negative values represent an increase in the risk of recurrent AOM.

Figures and Tables -
Table 3. The effect of pneumococcal conjugate vaccination on recurrent acute otitis media