Summary of findings for the main comparison. Pneumococcal conjugate vaccine versus control vaccine for preventing acute otitis media.

Pneumococcal conjugate vaccine versus control vaccine for preventing acute otitis media
Patient or population: infants (predominantly < 6 months of age) and older children (aged 1 to 7 years) Settings: community (Finland, the Netherlands, Czech Republic and Slovakia, Israel, USA, Argentina, Colombia and Panama) Intervention: multivalent PCVs Comparison: control vaccine
PCV type	VE ‐ relative effect (95% CI)*	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Frequency of all‐cause AOM (co‐primary outcome)
CRM197‐PCV7in low‐risk infants	RRR: 6% (−4% to 16%) to 6% (4% to 9%)#	39,530 (2)	⊕⊕⊕⊕ high	Results are derived from 1 very large trial including 37,868 infants, Black 2000/Fireman 2003, and 1 smaller trial including 1662 infants, Eskola 2001/Palmu 2009, with low risk of bias.
CRM197‐PCV7in high‐risk infants	RRR: −5% (−25% to 12%)	944 (1)	⊕⊕⊕⊝ moderate1	Results are derived from 1 relatively small trial with low risk of bias (O'Brien 2008).
OMPC‐PCV7in low‐risk infants	RRR: −1% (−12% to 10%)	1666 (1)	⊕⊕⊕⊕ high	Results are derived from 1 trial with low risk of bias (Kilpi 2003).
PHiD‐CV10in low‐risk infants	RRR: 6% (−6% to 17%) to 15% (−1% to 28%)	12,454 (2)	⊕⊕⊕⊝ moderate2	Results are derived from 2 trials with low, Tregnaghi 2014/Sáez‐Llorens 2017, and unclear risk of bias (Vesikari 2016). AOM incidence rate in control group in 1 of the trials, Tregnaghi 2014/Sáez‐Llorens 2017, was low compared to the other studies (Table 2).
PHiD‐CV11in low‐risk infants	RRR: 34% (21% to 44%)	4968 (1)	⊕⊕⊕⊕ high	Results are derived from 1 trial with low risk of bias (Prymula 2006). AOM incidence rate in control group was low compared to other studies (Table 2).
Adverse effects (co‐primary outcome)
CRM197‐PCV7in low‐risk infants OMPC‐PCV7in low‐risk infants PHiD‐PC10/11 in low‐risk infants CRM197‐PCV7/9 and CRM197‐PCV7 plus TIVin older children	Mild local reactions and fever were common in both groups. These adverse events occurred more frequently in the PCV than in the control vaccine groups: redness (< 2.5 cm): 5% to 20% versus 0% to 16%, swelling (< 2.5 cm): 5% to 12% versus 0% to 8%, and fever (< 39 °C): 15% to 44% versus 8% to 25%. More severe redness (> 2.5 cm), swelling (> 2.5 cm), and fever (> 39 °C) occurred less frequently (0% to 0.9%, 0.1% to 1.3%, and 0.4% to 2.5%, respectively in children receiving PCV) and did not differ significantly between PCV and control vaccine groups. Pain/tenderness was reported more frequently in children receiving PCV than in those receiving control vaccines: 3% to 38% versus 0% to 8%. Serious adverse events judged causally related to vaccination were rare and did not differ significantly between vaccine groups. No fatal serious adverse event judged causally related to vaccination was reported.	77,389 (9)	⊕⊕⊕⊕ high	Results are derived from 9 trials with low risk of bias.
Frequency of pneumococcal AOM
CRM197‐PCV7in low‐risk infants	RRR: 20% (7% to 31) to 34% (21% to 45%)	1662 (1)	⊕⊕⊕⊕ high	Results are derived from 1 trial with low risk of bias (Eskola 2001/Palmu 2009).
OMPC‐PCV7in low‐risk infants	RRR: 25% (11% to 37%)	1666 (1)	⊕⊕⊕⊕ high	Results are derived from 1 trial with low risk of bias (Kilpi 2003).
PHiD‐CV10in low‐risk infants	RRR: 53% (16% to 74%)	7359 (1)	⊕⊕⊕⊕ high	Results are derived from 1 trial with low risk of bias (Tregnaghi 2014/Sáez‐Llorens 2017).
PHiD‐CV11in low‐risk infants	RRR: 52% (37% to 63%)	4968 (1)	⊕⊕⊕⊕ high	Results are derived from 1 trial with low risk of bias (Prymula 2006).
Frequency of recurrent AOM (defined as 3 or more AOM episodes in 6 months or 4 or more in 1 year)
CRM197‐PCV7in low‐risk infants	RRR: 9% (−12% to 27%) to 10% (7% to 13%)	39,530 (2)	⊕⊕⊕⊕ high	Results are derived from 1 very large trial including 37,868 infants, Black 2000/Fireman 2003, and 1 smaller trial including 1662 infants, Eskola 2001/Palmu 2009, with low risk of bias.
PHiD‐CV11in low‐risk infants	RRR: 56% (−2% to 80%)	4968 (1)	⊕⊕⊕⊝ moderate3	Results are derived from 1 trial with low risk of bias (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. *For readability purposes, absolute rates (episodes/person‐year and incidence rate differences) are displayed in Table 1. # Depending on whether the outcome was assessed by a composite of positive culture or positive pneumolysin polymerase chain reaction (PCR) or by positive culture only or whether ITT or per‐protocol analysis was performed.

¹We downgraded the quality of the evidence from high to moderate due to imprecise effect estimate (only one trial with relatively small sample size).
 ²We downgraded the quality of the evidence from high to moderate due to study limitations (risk of bias) and imprecise effect estimates.
 ³We downgraded the quality of the evidence from high to moderate due to the imprecise effect estimate.

AOM: acute otitis media; CI: confidence interval; CRM197‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197; OMPC‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to the outer membrane protein complex of Neisseria meningitidis serogroup B; PCV: pneumococcal conjugate vaccine; PHiD‐CV10: 10‐valent pneumococcal conjugate vaccine conjugated to protein D (surface lipoprotein of non‐typeable Haemophilus influenzae); PHiD‐CV11: 11‐valent pneumococcal conjugate vaccine conjugated to protein D (surface lipoprotein of non‐typeable Haemophilus influenzae); RRR: relative risk reduction; TIV: trivalent influenza vaccine; VE: vaccine efficacy