Pneumococcal conjugate vaccines for preventing acute otitis media in children

Joline LH de Sévaux; Roderick P Venekamp; Vittoria Lutje; Eelko Hak; Anne GM Schilder; Elisabeth AM Sanders; Roger AMJ Damoiseaux

doi:10.1002/14651858.CD001480.pub6

Pneumococcal conjugate vaccines for preventing acute otitis media in children

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Versión publicada: 24 noviembre 2020 Historial de versiones

https://doi.org/10.1002/14651858.CD001480.pub6

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Abstract

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Background

Prior to introducing pneumococcal conjugate vaccines (PCVs), Streptococcus pneumoniae was most commonly isolated from the middle ear fluid of children with acute otitis media (AOM). Reducing nasopharyngeal colonisation of this bacterium by PCVs may lead to a decline in AOM. The effects of PCVs deserve ongoing monitoring since studies from the post‐PCV era report a shift in causative otopathogens towards non‐vaccine serotypes and other bacteria. This updated Cochrane Review was first published in 2002 and updated in 2004, 2009, 2014, and 2019.

Objectives

To assess the effect of PCVs in preventing AOM in children up to 12 years of age.

Search methods

We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Web of Science, and two trials registers, ClinicalTrials.gov and WHO ICTRP, to 11 June 2020.

Selection criteria

Randomised controlled trials of PCV versus placebo or control vaccine.

Data collection and analysis

We used the standard methodological procedures expected by Cochrane. The primary outcomes were frequency of all‐cause AOM and adverse effects. Secondary outcomes included frequency of pneumococcal AOM and frequency of recurrent AOM (defined as three or more AOM episodes in six months or four or more in one year). We used GRADE to assess the certainty of the evidence.

Main results

We included 15 publications of 11 trials (60,733 children, range 74 to 37,868 per trial) of 7‐ to 11‐valent PCVs versus control vaccines (meningococcus type C vaccine in three trials, and hepatitis A or B vaccine in eight trials). We included one additional publication of a previously included trial for this 2020 update. We did not find any relevant trials with the newer 13‐valent PCV. Most studies were funded by pharmaceutical companies. Overall, risk of bias was low. In seven trials (59,415 children), PCVs were administered in early infancy, whilst four trials (1318 children) included children aged one year and over who were either healthy or had a history of respiratory illness. There was considerable clinical heterogeneity across studies, therefore we reported results from individual studies.

PCV administered in early infancy

PCV7

The licenced 7‐valent PCV with CRM197 as carrier protein (CRM197‐PCV7) was associated with a 6% (95% confidence interval (CI) −4% to 16%; 1 trial; 1662 children) and 6% (95% CI 4% to 9%; 1 trial; 37,868 children) relative risk reduction (RRR) in low‐risk infants (moderate‐certainty evidence), but was not associated with a reduction in all‐cause AOM in high‐risk infants (RRR −5%, 95% CI −25% to 12%). PCV7 with the outer membrane protein complex of Neisseria meningitidis serogroup B as carrier protein (OMPC‐PCV7) was not associated with a reduction in all‐cause AOM (RRR −1%, 95% CI −12% to 10%; 1 trial; 1666 children; low‐certainty evidence).

CRM197‐PCV7 and OMPC‐PCV7 were associated with 20% (95% CI 7% to 31%) and 25% (95% CI 11% to 37%) RRR in pneumococcal AOM, respectively (2 trials; 3328 children; high‐certainty evidence), and CRM197‐PCV7 with 9% (95% CI −12% to 27%) and 10% (95% CI 7% to 13%) RRR in recurrent AOM (2 trials; 39,530 children; moderate‐certainty evidence).

PHiD‐CV10/11

The effect of a licenced 10‐valent PCV conjugated to protein D, a surface lipoprotein of Haemophilus influenzae, (PHiD‐CV10) on all‐cause AOM in healthy infants varied from 6% (95% CI −6% to 17%; 1 trial; 5095 children) to 15% (95% CI −1% to 28%; 1 trial; 7359 children) RRR (low‐certainty evidence). PHiD‐CV11 was associated with 34% (95% CI 21% to 44%) RRR in all‐cause AOM (1 trial; 4968 children; moderate‐certainty evidence).

PHiD‐CV10 and PHiD‐CV11 were associated with 53% (95% CI 16% to 74%) and 52% (95% CI 37% to 63%) RRR in pneumococcal AOM (2 trials; 12,327 children; high‐certainty evidence), and PHiD‐CV11 with 56% (95% CI −2% to 80%) RRR in recurrent AOM (1 trial; 4968 children; low‐certainty evidence).

PCV administered at a later age

PCV7

We found no evidence of a beneficial effect on all‐cause AOM of administering CRM197‐PCV7 in children aged 1 to 7 years with a history of respiratory illness or frequent AOM (2 trials; 457 children; moderate‐certainty evidence) and CRM197‐PCV7 combined with a trivalent influenza vaccine in children aged 18 to 72 months with a history of respiratory tract infections (1 trial; 597 children; moderate‐certainty evidence).

CRM197‐PCV9

In 1 trial including 264 healthy daycare attendees aged 1 to 3 years, CRM197‐PCV9 was associated with 17% (95% CI −2% to 33%) RRR in parent‐reported all‐cause otitis media (very low‐certainty evidence).

Adverse events

Nine trials reported on adverse effects (77,389 children; high‐certainty evidence). Mild local reactions and fever were common in both groups, and occurred more frequently in PCV than in 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 or tenderness, or both, was reported more frequently in PCV than in control vaccine groups: 3% to 38% versus 0% to 8%. Serious adverse events judged to be causally related to vaccination were rare and did not differ significantly between groups, and no fatal serious adverse event judged causally related to vaccination was reported.

Authors' conclusions

Administration of the licenced CRM197‐PCV7 and PHiD‐CV10 during early infancy is associated with large relative risk reductions in pneumococcal AOM. However, the effects of these vaccines on all‐cause AOM is far more uncertain based on low‐ to moderate‐certainty evidence. We found no evidence of a beneficial effect on all‐cause AOM of administering PCVs in high‐risk infants, after early infancy, and in older children with a history of respiratory illness. Compared to control vaccines, PCVs were associated with an increase in mild local reactions (redness, swelling), fever, and pain and/or tenderness. There was no evidence of a difference in more severe local reactions, fever, or serious adverse events judged to be causally related to vaccination.

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Plain language summary

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Pneumococcal vaccination for preventing acute middle ear infections in children

Review question

We reviewed the evidence for the effect of vaccination against Streptococcus pneumoniae (pneumococcus, a type of bacterium) for preventing acute middle ear infections in children.

Background

Before nationwide implementation of vaccination against S pneumoniae with pneumococcal conjugate vaccines (PCVs), pneumococcus was the most frequent cause of acute middle ear infections in children. Vaccination against this bacterium with PCVs may therefore lead to fewer acute middle ear infections in children. However, ongoing monitoring of the effects of PCVs on acute middle ear infections is warranted, since recent studies report a shift in bacteria causing acute middle ear infections towards pneumococcal types not included in the vaccines and other bacteria.

Study characteristics

The evidence is current up to 11 June 2020. We included 11 trials of PCVs versus control vaccines (meningococcus type C conjugate vaccine in three trials, and hepatitis A or B vaccine in eight trials) involving a total of 60,733 children. The PCVs used in the trials contained 7 to 11 different types of pneumococcus. None of the trials used the newer PCV containing 13 different types. Most trials were funded by pharmaceutical companies. Overall, risk of bias was low. In seven trials (59,415 children), children received PCVs in early infancy, whilst four trials included 1318 children aged one year and over who were either healthy or who had previous respiratory illness.

Key results

When a licenced vaccine containing seven different types of pneumococcus (CRM197‐PCV7) was given during early infancy, the risk of experiencing acute middle ear infections increased by 5% in high‐risk infants and decreased by 6% in low‐risk infants. When administrating a licenced vaccine containing 10 types of pneumococcus together with a carrier protein from another bacterium called Haemophilus influenzae (PHiD‐CV10), the risk of experiencing acute middle ear infections decreased by 6% to 15%, however neither of these estimates reached significance.

Giving PCV7 after early infancy (children aged one year and above) and in older children with a history of respiratory illness or frequent acute middle ear infections was not associated with reductions in acute middle ear infections.

Mild local reactions (redness, swelling), fever, and pain/tenderness were common and occurred more frequently in children receiving PCV than in those receiving control vaccines. More severe local reactions (redness and swelling > 2.5 cm) and fever (> 39 °C) occurred far less frequently and did not differ between vaccine groups. Serious adverse events judged to have been related to vaccination were rare and did not differ significantly between vaccine groups.

Certainty of the evidence

We assessed the certainty of the evidence for CRM197‐PCV7 in early infancy to be moderate (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate). We judged the certainty of the evidence for PHiD‐CV10 to be low (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). We judged the certainty of the evidence for PCV7 in older children with or without a history of respiratory illness to be moderate (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate).

Authors' conclusions

Implications for practice

The current evidence from randomised controlled trials (RCTs) indicates that, albeit associated with large relative risk reductions in pneumococcal acute otitis media (AOM), the effect of administration of the licenced CRM197‐PCV7 and PHiD‐CV10 in healthy, low‐risk infants on AOM is derived from low‐ to moderate‐certainty evidence and is therefore far more uncertain. In addition, we found no evidence of a beneficial effect on all‐cause AOM of administering PCVs in high‐risk infants, after early infancy, and in older children with a history of respiratory illness.

However, global postmarketing studies of these vaccines and of the licenced CRM197‐PCV13 suggest that the impact (i.e. both direct and indirect effects) of pneumococcal conjugate vaccines (PCVs) administered in infancy on AOM may be substantial. Furthermore, it should be noted that the decision of whether or not to implement PCV should not come from AOM studies only, but also from studies that see and show the big picture, including data on invasive pneumococcal disease such as pneumonia, bacteraemia, and meningitis.

Compared to control vaccines, PCVs were associated with an increase in mild local reactions (redness, swelling), fever, and pain/tenderness. However, we found no evidence of a difference in (far less frequently occurring) more severe local reactions, fever, or serious adverse events judged to be causally related to vaccination.

Implications for research

Since most countries across the world have implemented PCV in nationwide immunisation programmes, future RCTs comparing PCVs versus control vaccines are unlikely to be performed. Whilst there is some observational evidence of a difference in effects on AOM between PHiD‐CV10 and the newer CRM197‐PCV13 (Gisselsson‐Solen 2017), future trials may compare the efficacy of various types of PCVs. More importantly, future research will likely shed a light on the effects of other vaccines to prevent AOM, including (protein‐based) vaccines directed at Streptococcus pneumoniae (Hammitt 2019), as well as other pathogens including non‐typeable Haemophilus influenzae and Moraxella catarrhalis (Pettigrew 2017).

Whether any decline in AOM will continue or wane over time due to replacement is relevant and deserves ongoing monitoring. Besides a reduction of nasopharyngeal vaccine‐type serotypes, which is presumed to induce herd effects, replacing pneumococcal serotypes may not only lead to replacement disease in vaccines, but also in the population. Continuing surveillance of nasopharyngeal carriage and pneumococcal disease in both the short and long term (Spijkerman 2012), in different settings and geographic locations, is therefore of the utmost importance.

Summary of findings

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Summary of findings 1. Pneumococcal conjugate vaccine versus control vaccine for preventing acute otitis media in children

PCV type	VE ‐ relative effect (95% CI)*	No. of participants (studies)	Certainty of evidence	Comments
Pneumococcal conjugate vaccine versus control vaccine for preventing acute otitis media in children
Patient or population: infants (predominantly < 6 months of age) and older children (aged 1 to 7 years) Settings: community (Finland, the Netherlands, the Czech Republic and Slovakia, Israel, the USA, Argentina, Colombia, and Panama) Intervention: multivalent PCVs Comparison: control vaccine
Frequency of all‐cause acute otitis media
CRM197‐PCV7in low‐risk infants	RRR: 6% (−4% to 16%) to 6% (4% to 9%)^#	39,530 (2 RCTs)	⊕⊕⊕⊝ Moderate^a	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.
CRM197‐PCV7in high‐risk infants	RRR: −5% (−25% to 12%)	944 (1 RCT)	⊕⊕⊝⊝ Low^b	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 RCT)	⊕⊕⊝⊝ Low^b	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 RCTs)	⊕⊕⊝⊝ Low^c	Results are derived from 2 trials with low, Tregnaghi 2014/Sáez‐Llorens 2017, and unclear risk of bias (Vesikari 2016/Karppinen 2019). AOM incidence rate in the control group of 1 trial, Tregnaghi 2014/Sáez‐Llorens 2017, was low compared to other studies (Table 1).
PHiD‐CV11in low‐risk infants	RRR: 34% (21% to 44%)	4968 (1 RCT)	⊕⊕⊕⊝ Moderate^d	Results are derived from 1 trial with low risk of bias (Prymula 2006). AOM incidence rate in the control group was low compared to other studies (Table 1).
Adverse effects
CRM197‐PCV7in low‐risk infants OMPC‐PCV7in low‐risk infants PHiD‐PC10 and PHiD‐PC11 in low‐risk infants CRM197‐PCV7/9 and CRM197‐PCV7 plus TIVin older children	Mild local reactions and fever were common in both groups, occurring 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 to be causally related to vaccination were rare and did not differ significantly between vaccine groups. No fatal serious adverse event judged to be causally related to vaccination was reported.	77,389 (9 RCTs)	⊕⊕⊕⊕ High	Results are derived from 9 trials with low risk of bias.
Frequency of pneumococcal acute otitis media
CRM197‐PCV7in low‐risk infants	RRR: 20% (7% to 31) to 34% (21% to 45%)	1662 (1 RCT)	⊕⊕⊕⊕ 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 RCT)	⊕⊕⊕⊕ 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 RCT)	⊕⊕⊕⊕ 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 RCT)	⊕⊕⊕⊕ High	Results are derived from 1 trial with low risk of bias (Prymula 2006).
Frequency of recurrent acute otitis media (defined as 3 or more acute otitis media 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 RCTs)	⊕⊕⊕⊝ Moderate^e	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, both with low risk of bias.
PHiD‐CV11in low‐risk infants	RRR: 56% (−2% to 80%)	4968 (1 RCT)	⊕⊕⊝⊝ Low^f	Results are derived from 1 trial with low risk of bias (Prymula 2006).
*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 and positive pneumolysin polymerase chain reaction (PCR) or by positive culture only, or whether ITT or per‐protocol analysis was performed.
GRADE (certainty in the evidence) High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: 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 certainty: Any estimate of effect is very uncertain.
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) RCT: randomised controlled trial RRR: relative risk reduction TIV: trivalent influenza vaccine VE: vaccine efficacy ^aWe downgraded the certainty of the evidence from high to moderate due to imprecise effect estimate and study limitations (risk of bias). ^bWe downgraded the certainty of the evidence from high to low due to the very imprecise effect estimate. ^cWe downgraded the certainty of the evidence from high to low due to study limitations (risk of bias) and imprecise effect estimates. ^dWe downgraded the certainty of the evidence from high to moderate due to indirectness of evidence (low AOM incidence rate in the control group compared to other studies, most likely due to methodological differences with other studies). ^eWe downgraded the certainty of the evidence from high to moderate due to imprecise effect estimate. ^fWe downgraded the certainty of the evidence from high to low due to imprecise effect estimate and indirectness of evidence (low AOM incidence rate in the control group compared to other studies, most likely due to methodological differences with other studies).

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1. Effect of pneumococcal conjugate vaccination on frequency of all‐cause acute otitis media episodes

	Episodes/person‐year		Incidence rate difference ‐ episodes per person‐year (95% CI)	VE expressed as relative reduction in risk (95% CI)^a	Episodes/person‐year		Incidence rate difference ‐ episodes per person‐year (95% CI)	VE expressed as relative reduction in risk (95% CI)^a
	Intention‐to‐treat				Per‐protocol
	Treatment	Control		VE expressed as relative reduction in risk (95% CI)^a	Treatment	Control		VE expressed as relative reduction in risk (95% CI)^a
PCV administered in early infancy
*CRM197‐PCV7*
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^d	6% (−4% to 16%)
O'Brien 2008^b	1.43	1.36	0.07 (−0.05 to 0.18)	−5% (−25% to 12%)^c	1.35	1.35	0.00 (−0.13 to 0.14)	0% (−21% to 17%)
*OMPC‐PCV7*
Kilpi 2003	‐	‐	‐	‐	‐	‐	‐	−1%^h (−12% to 10%)
*PHiD‐PC10 and PHiD‐PC11*
Tregnaghi 2014 Sáez‐Llorens 2017	0.03	0.04	−0.01 (−0.01 to 0.00)	15% (−1% to 28%)	‐	‐	‐	13% (−5% to 28%)
Vesikari 2016^b Karppinen 2019^e	‐ ‐	‐ ‐	‐ ‐	‐ ‐	0.99 1.0	1.01 1.3	−0.02^d −0.3 (−0.7 to 0.1)	6% (−6% to 17%) 23% (0% to 40%)
Prymula 2006	‐	‐	‐	‐	0.08	0.13	−0.04^d	34% (21% to 44%)
PCV administered at a later age
*CRM197‐PCV7 followed by PPV23*
Veenhoven 2003	‐	‐	‐	−25% (−57% to 1%)	1.1	0.83	−0.27^d	−29%^h (−62% to −2%)
van Kempen 2006	‐	‐	‐	‐	0.78	0.67	−0.11^d	−16%^h (−96% to 31%)
*CRM197‐PCV7/TIV*
Jansen 2008	‐	‐	‐	‐	‐	‐	‐	57% (6% to 80%)^f
*CRM197‐PCV9*
Dagan 2001	‐	‐	‐	‐	0.66	0.79	−0.14 (−0.29 to 0.02)	17% (−2% to 33%)
CI: confidence interval CRM197‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV7/TIV: trivalent influenza vaccine plus 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV9: 9‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 HBV: hepatitis B virus 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) PPV23: 23‐valent pneumococcal polysaccharide vaccine TIV: trivalent influenza vaccine VE: vaccine efficacy ^aPositive effect estimates indicate a relative reduction in the risk (e.g. 6% means that the vaccine reduces the risk by 6%); negative effect estimates indicate a relative increase in the risk (e.g. −5% means that the vaccine increases the risk by 5%). ^bCluster‐randomised controlled trial. ^cDefined as primary efficacy analysis. Analysis is not entirely according to intention‐to‐treat principle, as 88/944 children were not included in the analysis due to not meeting strict chart review criteria. ^d95% CI could not be calculated, as person‐time across treatment groups was not reported. ^eRespiratory tract infections with acute otitis media was used as the outcome measure. The PHiD‐CV10 and control vaccine groups were statistically different from each other in terms of type of residential area, presence of older siblings, and socioeconomic status of the family. ^fIndex group: CRM197‐PCV7/TIV, control: HBV/placebo; VE placebo/TIV versus HBV/placebo: 71% (95% CI 30% to 88%), that is larger VE placebo/TIV versus HBV/placebo than CRM197‐PCV7/TIV versus HBV/placebo. ^hnegative values for VE expressed as relative reduction in risk represent an increase in the risk for acute otitis media.

Background

Description of the condition

Acute otitis media (AOM), defined as the presence of middle ear fluid together with one or more signs or symptoms of acute middle ear inflammation such as otalgia, otorrhoea, fever, or irritability, is one of the most common diseases in childhood and imposes a large burden on public health (Lieberthal 2013). Global AOM incidence rates are highest in children 1 to 4 years of age, with a peak incidence in 6‐ to 11‐month‐old infants (Monasta 2012). By the age of two years, up to 5% of all children have experienced recurrent AOM, defined as three or more AOM episodes in six months, or four or more in one year (Kvaerner 1997; Lieberthal 2013). The three main bacterial pathogens isolated from the middle ear fluid of children with AOM collected before the widespread use of pneumococcal conjugate vaccines (PCVs) were Streptococcus pneumoniae (25% to 39%), (non‐typeable) Haemophilus influenzae (12% to 23%), and Moraxella catarrhalis (4% to 15%) (Bluestone 1992; Heikkinen 1999; Jacobs 1998; Luotonen 1981). Recent studies have shown that nationwide implementation of PCVs may have changed the frequency of the causative otopathogens involved in AOM towards pneumococcal serotypes not included in the vaccines and other bacteria including non‐typeable H influenzae (Allemann 2017; Barenkamp 2017; Ben‐Shimol 2019; Casey 2013; Coker 2010; Kaur 2017; Somech 2011; Tamir 2015; Wiertsema 2011).

Description of the intervention

The marginal benefits of antibiotics for AOM in low‐risk populations (Rovers 2006; Venekamp 2015); the increasing problem of bacterial resistance against antibiotics (Laxminarayan 2013); and the high estimated direct and indirect annual costs associated with AOM have prompted a search for effective vaccines to prevent this condition (Ahmed 2014; Boonacker 2011). With S pneumoniae (pneumococcus) being a common causative pathogen in childhood AOM and pneumonia, and one of the most frequent causes of invasive bacterial disease such as bacteraemia and meningitis, research has focused on the prevention of pneumococcal infections by pneumococcal vaccines. Pneumococcal polysaccharide vaccines (PPVs) have been available for decades, but have been shown to be poorly immunogenic in children aged up to two years, who are most prone to pneumococcal infections. In the most recent versions of this review, no further attention has been paid to the effect of PPVs, which were described in prior versions of this review (Straetemans 2003).

The first pneumococcal conjugate vaccines (PCVs), in which the pneumococcal capsular serotypes are covalently conjugated to carrier proteins, were developed in the 1990s and proved to be adequately immunogenic in infants and toddlers (Dagan 1997; Eskola 1999; Shinefield 1999). Over the past decades, various PCVs have been developed for use in children including:

licenced 7‐valent PCV containing the polysaccharides of seven serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) conjugated to the diphtheria‐derived carrier protein CRM197 (CRM197‐PCV7);
7‐valent PCV with the outer membrane complex of Neisseria meningitidis serogroup B as carrier protein (OMPC‐PCV7);
9‐valent PCV containing the capsular polysaccharides of serotypes 1 and 5 in addition to those included in PCV7, conjugated to CRM197 (CRM197‐PCV9);
licenced 10‐valent PCV containing the capsular polysaccharides of 10 serotypes (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F) mostly conjugated to protein D, which is a surface lipoprotein of H influenzae (PHiD‐CV10);
11‐valent containing the capsular polysaccharides of serotype 3 as well as those included in PHiD‐CV10 (PHiD‐CV11); and
licenced 13‐valent PCV containing the capsular polysaccharides of 13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) conjugated to CRM197 (CRM197‐PCV13).

How the intervention might work

Early and dense colonisation of the nasopharynx with bacterial otopathogens, including S pneumoniae, increases the risk of AOM substantially (Faden 1997; Leach 1994; Schilder 2016). As a consequence, reducing or eliminating nasopharyngeal colonisation of S pneumoniae by PCVs may lead to reductions in AOM incidence. In recent years, evidence has accumulated that PCVs might also disrupt the continuum of evolution from pneumococcal‐associated otitis media (OM) towards chronic/recurrent OM by prevention of early vaccine‐serotype AOM and thereby reducing subsequent and more complex disease caused by non‐vaccine serotypes and non‐typeable H influenzae (Ben‐Shimol 2014; Dagan 2016).

Why it is important to do this review

With AOM amongst the most common diseases in early childhood, the need for a vaccine to effectively prevent AOM is high. Over the past decades various randomised controlled trials have been performed to assess the effects of pneumococcal vaccination to prevent AOM. From 2009 onwards, two multivalent PCVs (PHiD‐CV10 and CRM197‐PCV13) have been licenced and are being implemented in nationwide immunisation programmes worldwide (WHO 2012). These new vaccines may have an increased benefit in preventing AOM (Marom 2014; O'Brien 2009; Soysal 2020). As such, it was important to provide an up‐to‐date systematic review on the effects of PCVs on preventing AOM. This review is an update of a Cochrane Review first published in 2002 (Straetemans 2002), and updated in 2004 (Straetemans 2004), 2009 (Jansen 2009), 2014 (Fortanier 2014), and 2019 (Fortanier 2019).

Objectives

To assess the effect of PCVs in preventing AOM in children up to 12 years of age.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs), irrespective of type, assessing the effect of pneumococcal conjugate vaccines (PCV) versus placebo or control vaccine in preventing acute otitis media (AOM) with a minimum follow‐up duration of six months. As per previous versions of this review, we excluded studies that did not report outcome data relevant to this review.

Types of participants

Children aged up to 12 years.

Types of interventions

PCV versus placebo or control vaccine.

Types of outcome measures

We extracted data for the following predefined outcomes of interest.

Primary outcomes

Frequency of all‐cause AOM episodes, defined as AOM irrespective of causative pathogen. We considered this to be the most relevant outcome for children, parents, and clinicians.
Adverse effects including local (redness, swelling) and systemic reactions (fever), pain/tenderness, and serious adverse events (SAEs) judged to be causally related to vaccination.

Secondary outcomes

Frequency of pneumococcal AOM.
Frequency of pneumococcal serotype‐specific AOM (including vaccine serotype, non‐vaccine serotype, and cross‐reactive serotypes which are non‐vaccine serotypes with a serogroup that is included in the vaccine).
Frequency of recurrent AOM (defined as three or more episodes in six months or four or more in one year).

Search methods for identification of studies

The Cochrane Acute Respiratory Infections Group (2018 search update) and Cochrane Infectious Disease Group (2019 and 2020 search update) Information Specialists conducted systematic searches for RCTs and controlled clinical trials. There were no language, publication year, or publication status restrictions. The latest search was conducted on 11 June 2020.

Electronic searches

For the 2014 review update, we used the search strategy presented in Appendix 1.

For the 2020 and 2019 updates, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 6, 2020), which contains the Cochrane Acute Respiratory Infections Specialised Register; MEDLINE (Ovid) (1995 to 11 June 2020); Embase (Elsevier) (1995 to 11 June 2020); CINAHL (EBSCO) (Cumulative Index to Nursing and Allied Health Literature) (2007 to 11 June 2020); LILACS (BIREME) (Latin American and Caribbean Health Science Information database) (2007 to 11 June 2020), and Science Citation Index Expanded (SCI‐EXPANDED), Conference Proceedings Citation Index‐Science (CPCI‐S), and Current Chemical Reactions (CCR‐EXPANDED) (all three from the Web of Science; Clarivate Analytics) (2007 to 11 June 2020).

We used the search strategy presented in Appendix 2 to search CENTRAL and MEDLINE. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐ and precision‐maximising version (2008 revision); Ovid format (Lefebvre 2011). We adapted the search strategy to search Embase (Appendix 3), CINAHL (Appendix 4), LILACS (Appendix 5), and Web of Science (Appendix 6).

Searching other resources

To increase the yield of relevant studies, two review authors (JLHdS, RPV for the 2020 update) reviewed the reference lists of all relevant studies and review articles retrieved. We searched the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov/) (Appendix 7) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/trialsearch) (Appendix 8) on 4 September 2020 for completed and ongoing trials. We also searched the internet (via Google using the search terms 'pneumococcal conjugate vaccination for acute otitis media trial') and the extended abstracts published in the Recent Advances in Otitis Media (grey literature) on 4 September 2020 for any additional trials.

Data collection and analysis

Selection of studies

Two review authors (JLHdS, RPV for the 2020 update) independently screened the titles and abstracts identified by the database searches and reviewed the full text of those titles and abstracts deemed potentially relevant against the inclusion criteria. Any disagreements were resolved by discussion.

Data extraction and management

Two review authors (JLHdS, RPV for the 2020 update) independently extracted data from the included studies. Any disagreements were resolved by discussion.

Assessment of risk of bias in included studies

Two review authors (JLHdS, RPV for the 2020 update) independently assessed the methodological quality of the included trials. Any disagreements were resolved by discussion. We assessed the methodological quality of included studies using the 'Risk of bias' tool as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We judged the following domains as low, high, or unclear risk of bias: random sequence generation (selection bias), concealment of allocation (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other sources of bias.

Measures of treatment effect

We expressed estimates of treatment effects as relative risks/hazard ratios with accompanying 95% confidence intervals (CIs). Vaccine efficacy was estimated as 1 minus the relative risk/hazard ratio (relative risk reduction (RRR)).

Unit of analysis issues

We included all types of RCTs. In the case of cluster‐randomised trials, we considered potential differences between the intervention effects being estimated and checked whether clustering was taken into account in the analysis of the individual trials.

Dealing with missing data

For each trial, we determined the number of missing data and whether the authors took duration of follow‐up (and censoring) of individual participants into account in their statistical analyses.

Assessment of heterogeneity

We first assessed clinical heterogeneity across trials by reviewing the differences in the types of participants recruited, interventions used, and outcomes measured. We did not pool studies where clinical heterogeneity made it of no use to do so. Where studies were sufficiently homogeneous, we proposed to assess statistical heterogeneity for each outcome by visually inspecting the forest plots and by using the Chi² test and the I² statistic.

Assessment of reporting biases

We proposed to assess reporting bias as within‐study (outcome reporting) and between‐study reporting (publication) bias (Higgins 2011).

Outcome reporting bias

We searched the internet, ClinicalTrials.gov, and the WHO ICTRP for available study protocols to determine whether the outcomes reported in the studies were predefined, and whether all outcomes listed in the study protocol were reported in the trial publications. Where information was insufficient to judge risk of bias, we classified the risk of bias as unclear (Higgins 2011).

Publication bias

We proposed a more formal method of assessing reporting bias, that is by creating funnel plots, if sufficient trials (10 or more) were available for a given outcome.

Data synthesis

We primarily analysed the available data according to the intention‐to‐treat principle, that is by analysing all participants in the groups to which they were originally randomised. As a secondary analysis, we presented data based on a per‐protocol analysis.

Where possible, we proposed conducting meta‐analyses using Review Manager 5 by calculating treatment effects with the Mantel‐Haenszel method, using a fixed‐effect model where no substantial statistical heterogeneity was present (I² < 50%) (Review Manager 2014). If substantial statistical heterogeneity was detected and unresolved by sensitivity analysis, we proposed to calculate treatment effects using a random‐effects (DerSimonian and Laird) model to provide more conservative effect estimates. Where clinical heterogeneity precluded meta‐analyses, we reported the effect estimates as presented by the individual trials. If possible, we reported the incidences of the various outcomes in the study arms together with the vaccine efficacy estimates, with 95% CIs.

We proposed the following methods to conduct meta‐analyses. The generalised Cox proportional hazard method proposed by Andersen 1982 is regarded as the most appropriate to assess the effect of PCVs on AOM (Jahn‐Eimermacher 2007). Under the assumption that the hazard rate is proportional between both groups over time, and that the risk of AOM is not affected by previous episodes (although this is untrue), this model takes all available information into account, that is all episodes (including recurrences), differences in individual patient follow‐up time, and time until a case of AOM (Jahn‐Eimermacher 2007). However, information on individual follow‐up time until the first, second, third, etc. case of AOM is difficult to obtain for each study to be included in the meta‐analysis. Poisson regression is based on the assumption of a constant risk of AOM over time, and that this risk is not affected by previous episodes of AOM. This method only requires the total follow‐up time and total number of episodes, and therefore appears to be a more feasible method for meta‐analysis. Furthermore, Poisson regression seems not to be affected by the deviation from a constant risk over time, having very similar results for the effect of PCVs on AOM to the Andersen‐Gill approach (Jahn‐Eimermacher 2007). For Poisson regression, the treatment effect is measured as a rate ratio defined as follows: (total AOM episodes in pneumococcal vaccination group divided by the number of children in the pneumococcal vaccination group multiplied by the follow‐up time in months) divided by (total AOM episodes in control group divided by the number of children in the control group multiplied by the follow‐up time in months) (McCullagh 1989).

Subgroup analysis and investigation of heterogeneity

Because the effect of PCVs on AOM may be influenced by the age at which the PCV was administered, occurrence of previous AOM or respiratory tract infection episodes, and by the type of PCV used, we described the studies accordingly, that is we stratified those with vaccination in early infancy versus those with vaccination later in childhood by type of PCV used.

Sensitivity analysis

We planned to carry out sensitivity analyses for risk of bias of the included studies to assess the robustness of review findings by excluding studies with high risk of bias (defined as high risk of bias for allocation concealment and high risk of attrition bias (overall loss to follow‐up of more than 20% or differential follow‐up observed, or both)) from meta‐analysis.

Summary of findings and assessment of the certainty of the evidence

We created summary of findings Table 1 for PCVs administered in early infancy using the following outcomes: frequency of all‐cause AOM episodes, adverse effects, frequency of pneumococcal AOM, and frequency of recurrent AOM (defined as three or more AOM episodes in six months or four or more in one year). We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of a body of evidence as it relates to the studies that contribute data to the meta‐analyses for the prespecified outcomes (Atkins 2004). We judged the certainty of the evidence as high, moderate, low, or very low. We assessed evidence from RCTs that did not have serious limitations as of high certainty. However, we downgraded the certainty of evidence to moderate, low, or very low based on the following factors: study limitations (risk of bias), inconsistency (consistency of results), imprecision (precision of results), indirectness of evidence (directness of evidence), and publication bias (existence of publication bias). We used the methods and recommendations described in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019), employing GRADEpro GDT software (GRADEpro GDT). We justified all decisions to down‐ or upgrade the certainty of evidence using footnotes, and made comments to aid the reader's understanding of the review where necessary.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies.

Results of the search

This review is an update of a Cochrane Review first published in 2002 (Straetemans 2002), and updated in 2004 (Straetemans 2004), 2009 (Jansen 2009), 2014 (Fortanier 2014), and 2019 (Fortanier 2019). In the 2019 review, which included studies up to March 2019, we included 11 RCTs reported in 14 publications (Black 2000/Fireman 2003; Dagan 2001; Eskola 2001/Palmu 2009; Jansen 2008; Kilpi 2003; O'Brien 2008; Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017; van Kempen 2006; Veenhoven 2003; Vesikari 2016).

For the 2019 update, we searched electronic databases (December 2013 to March 2019) and retrieved 374 records. After removal of duplicates, we assessed 225 records by title and abstract, and identified eight potentially eligible studies, which we obtained in full text. After reviewing the full texts, we excluded two publications that were additional analyses of the Eskola 2001 study but did not include new outcome data useful to this review (Palmu 2015a; Sarasoja 2013), and three publications that were secondary analyses of the Finnish invasive pneumococcal disease (FinIP) vaccine trial but did not report on any of our outcomes of interest (Palmu 2014; Palmu 2015b; Palmu 2018). This left three publications, Sáez‐Llorens 2017; Tregnaghi 2014; Vesikari 2016, relating to two RCTs, Tregnaghi 2014; Vesikari 2016, suitable for inclusion. Sáez‐Llorens 2017 was a further analysis of Tregnaghi 2014.

For this 2020 update, we searched electronic databases (March 2019 to June 2020) and retrieved 131 records. After de‐duplication, we assessed 79 unique records by title and abstract, and identified one additional potentially eligible study, which we obtained in full text. This study (Karppinen 2019) was suitable for inclusion and was included as secondary analysis of Vesikari 2016 (FinIP vaccine trial). See Figure 1.

Figure 1

Study flow diagram.

We did not identify additional relevant completed trials or any ongoing studies by scanning the reference lists of relevant systematic reviews or by searching the internet, the grey literature, or ClinicalTrials.gov and WHO ICTRP.

Included studies

See Characteristics of included studies table.

We included 11 RCTs reported in 15 publications (Black 2000/Fireman 2003; Dagan 2001; Eskola 2001/Palmu 2009; Jansen 2008; Kilpi 2003; O'Brien 2008; Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017; van Kempen 2006; Veenhoven 2003; Vesikari 2016/Karppinen 2019). We added two RCTs (reported in four publications) for the 2019 and 2020 updates (Tregnaghi 2014/Sáez‐Llorens 2017; Vesikari 2016/Karppinen 2019). The included trials involved a total of 60,733 children.

Study designs

Of the 11 included studies, nine were standard, individually randomised trials, and two were cluster‐RCTs (O'Brien 2008; Vesikari 2016). Both cluster‐RCTs took the cluster effect into account in their analyses.

Study populations (early infancy versus later in life)

In seven trials (Black 2000/Fireman 2003; Eskola 2001/Palmu 2009; Kilpi 2003; O'Brien 2008; Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017; Vesikari 2016/Karppinen 2019), PCVs were predominantly administered in children's first six months of life. Four trials assessed the effects of PCVs in children aged one year and over who were either healthy (Dagan 2001), or had a history of respiratory illness (Jansen 2008; van Kempen 2006; Veenhoven 2003). Three trials were conducted in Finland (Eskola 2001/Palmu 2009; Kilpi 2003; Vesikari 2016/Karppinen 2019), two in the USA (Black 2000/Fireman 2003; O'Brien 2008), two in the Netherlands (Jansen 2008; Veenhoven 2003), and the remaining in Belgium (van Kempen 2006), Israel (Dagan 2001), the Czech Republic and Slovakia (Prymula 2006), and Argentina, Colombia, and Panama (Tregnaghi 2014/Sáez‐Llorens 2017). Most of these countries had AOM diagnosis and management guidelines at the time of the study (Tamir 2017).

Interventions

Type of PCV used and co‐administration of other vaccines

In six trials, CRM197‐PCV7 was used as the intervention (Black 2000/Fireman 2003; Eskola 2001/Palmu 2009; Jansen 2008; O'Brien 2008; van Kempen 2006; Veenhoven 2003). In two studies, a booster dose with 23‐valent PPV (containing capsular polysaccharides of the serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F) was given to all children (van Kempen 2006; Veenhoven 2003). In one trial, CRM197‐PCV7 was administered together with a trivalent inactivated influenza vaccine (TIV) (Jansen 2008).

Four different interventions were used in five trials: OMPC‐PCV7 in Kilpi 2003 (a subset of these children received PPV23 as a booster dose); CRM197‐PCV9 in Dagan 2001; PHiD‐CV10 in Tregnaghi 2014/Sáez‐Llorens 2017 and Vesikari 2016/Karppinen 2019; and PHiD‐CV11 in Prymula 2006.

Comparator

Control vaccines were used as comparators in all trials. The comparator vaccine in three trials was meningococcus type C conjugate vaccine (10 µg of group C oligosaccharide conjugated to carrier protein CRM197; MenC) (Black 2000/Fireman 2003; Dagan 2001; O'Brien 2008), whilst hepatitis A or B vaccine was used in the remaining eight trials.

Outcome measures

Adverse effects were reported in nine trials including a total of 77,389 children (Black 2000/Fireman 2003; Dagan 2001; Eskola 2001/Palmu 2009; Jansen 2008; Kilpi 2003; Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017; Veenhoven 2003; Vesikari 2016/Karppinen 2019). Tregnaghi 2014/Sáez‐Llorens 2017 was part of the Clinical Otitis Media and Pneumonia Study (COMPAS; clinicaltrials.gov/show/NCT00466947), which assessed the efficacy and safety of PHiD‐CV10 against invasive pneumococcal disease, community‐acquired pneumonia, and AOM in 23,821 young Latin American children. Acute otitis media was studied in the Panama cohort only, which included 7357 children, whereas safety data were available for all 23,821 children.

Six trials applied a standardised diagnosis of AOM (Eskola 2001/Palmu 2009; Kilpi 2003; Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017; van Kempen 2006; Veenhoven 2003), and one trial used standardised AOM registration forms to be completed by general practitioners (Jansen 2008). In two trials, AOM episodes were extracted from a computerised data source containing all visits registered by physicians (Black 2000/Fireman 2003; O'Brien 2008). Two trials relied on parent‐reported AOM episodes (Dagan 2001; Vesikari 2016); Vesikari 2016 used parent‐reported, physician‐confirmed AOM as the outcome of interest. Karppinen 2019 used parent‐reported data (symptom diaries), data from study clinic visits, and data on hospitalisations from an electronic registry as outcome measures. Two trials assessed outcomes during influenza seasons (Jansen 2008; van Kempen 2006).

Seven trials also assessed the effect of PCVs on (serotype‐specific) pneumococcal AOM (Black 2000/Fireman 2003; Eskola 2001; Kilpi 2003; O'Brien 2008; Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017; Veenhoven 2003). Three studies cultured middle ear fluid from all AOM episodes (Eskola 2001; Kilpi 2003; Prymula 2006), and one trial cultured middle ear fluid by tympanocentesis when fluid was suspected in the middle ear (Tregnaghi 2014/Sáez‐Llorens 2017). One trial only cultured middle ear fluid from the first AOM episode by tympanocentesis or from spontaneously draining ears (Veenhoven 2003). Two trials assessed the effect on reported cultures that were obtained from spontaneously draining ears (Black 2000/Fireman 2003; O'Brien 2008).

Three trials reported the effects of PCVs on recurrent AOM (Black 2000/Fireman 2003; Eskola 2001; Prymula 2006). Three studies included all types of otitis media, including, but not exclusively AOM, as an outcome (Black 2000/Fireman 2003; Dagan 2001; O'Brien 2008).

Funding and conflicts of interest

Six trials were funded by pharmaceutical companies (Black 2000/Fireman; Eskola 2001/Palmu 2009; Kilpi 2003; Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017; Vesikari 2016/Karppinen 2019). Three trials reported receiving support from non‐commercial (governmental) sources, but study vaccines were supplied by pharmaceutical companies (Jansen 2008; van Kempen 2006; Veenhoven 2003). One trial was supported by both a pharmaceutical company and governmental funding (O'Brien 2008). One trial reported that study vaccines were supplied by a pharmaceutical company (Dagan 2001).

Brief overview of clinical heterogeneity across included studies

There was considerable clinical heterogeneity across the included trials. There were differences in the timing of PCV administration, that is trials administering PCV during infancy and trials administering PCV later in life. As such, study populations varied from healthy infants to those at high risk of AOM. Secondly, the number of pneumococcal serotypes present in the vaccines, the type of conjugate method used, and co‐administration of other vaccines differed substantially across trials. Study designs also varied, including both individually randomised controlled trials and cluster‐RCTs. Finally, large differences in outcome assessments and AOM definitions were observed, varying from 'passive' (chart review at the end of the trial) to 'active' (parents were instructed to visit a physician in case of AOM symptoms) outcome assessments and physician‐confirmed AOM episodes versus parent‐reported AOM episodes. Consequently, AOM incidence in the control groups varied widely across the studies administering PCV during infancy, from 0.13 to 1.3 episodes per person‐year. We therefore did not perform meta‐analyses.

Excluded studies

In the 2014 version of this review (Fortanier 2014), four studies were excluded because they (i) did not include a control vaccine (Gisselsson‐Solen 2011); (ii) did not report outcome data relevant for this review (Jokinen 2012); (iii) assessed the effect of PCV on otitis media with effusion rather than AOM (Le 2007); and (iv) reported the effect of PCV on suppurative otitis media in an abstract of a conference meeting (Roy 2011). In the 2019 update, a further five studies were excluded that did not report outcome data relevant for this review (Palmu 2014; Palmu 2015a; Palmu 2015b; Palmu 2018; Sarasoja 2013). We did not exclude any new studies in this 2020 update. See Characteristics of excluded studies table.

Ongoing studies

We did not identify any ongoing studies relevant to this review.

Risk of bias in included studies

We judged the methodological quality of the included studies to be moderate to high. The 'Risk of bias' assessment is presented graphically in Figure 2 and Figure 3. See Characteristics of included studies table.

Figure 2

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

Figure 3

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

Allocation

Eight trials described concealment of allocation adequately, whilst due to insufficient information we assessed this domain as unclear for three trials (Black 2000/Fireman 2003; Jansen 2008; Veenhoven 2003). We judged random sequence generation to be adequate in seven trials, whilst four trials provided insufficient information on methods of random sequence generation used (Black 2000/Fireman 2003; Dagan 2001; Jansen 2008; van Kempen 2006).

Blinding

Although all studies indicated that trials were double‐blinded, three trials provided insufficient information about how blinding was performed (Black 2000/Fireman 2003; Prymula 2006; Vesikari 2016/Karpinnen 2019).

Incomplete outcome data

We judged risk of attrition bias to be high in one trial (Vesikari 2016/Karppinen 2019), unclear in three trials (Black 2000/Fireman 2003; Jansen 2008; O'Brien 2008), and low in seven trials.

Selective reporting

We judged risk of reporting bias to be unclear in six trials, Black 2000/Fireman 2003; Dagan 2001; Eskola 2001/Palmu 2009; Kilpi 2003; van Kempen 2006; Veenhoven 2003, and low in the remaining five trials.

Other potential sources of bias

We judged risk of bias due to other sources (including balances in baseline characteristics, use of co‐intervention across groups, presence of formal sample size calculations, and (prespecified) interim analyses) as unclear in three trials, Black 2000/Fireman 2003; Kilpi 2003; O'Brien 2008, and low in the remaining eight trials.

Effects of interventions

See: Summary of findings 1 Pneumococcal conjugate vaccine versus control vaccine for preventing acute otitis media in children

Effect estimates of the various PCV types, stratified by the age at which PCVs were administered and the occurrence of previous AOM/respiratory tract infection (RTI) episodes (i.e. administration in early infancy versus later in life), on frequency of all‐cause AOM, (vaccine‐type) frequency of pneumococcal AOM, and frequency of recurrent AOM (defined as three or more AOM episodes in six months or four or more in one year), are summarised in Table 1, Table 2, and Table 3, respectively. The main results for PCVs administered in early infancy are described in summary of findings Table 1.

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Table 2. Effect of pneumococcal conjugate vaccination on frequency of pneumococcal acute otitis media episodes

	VE expressed as relative reduction in risk (95% CI)				VE expressed as relative reduction in risk (95% CI)
	Intention‐to‐treat				Per‐protocol
	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
*CRM197‐PCV7*
Black 2000^a Fireman 2003	‐ ‐	65% P = 0.04 ‐	‐ ‐	‐ ‐	‐ ‐	67% P = 0.08 ‐	‐ ‐	‐ ‐
Eskola 2001 Palmu 2009^b	‐ ‐	54% (41% to 64%) ‐	‐ ‐	‐ ‐	34% (21% to 45%) 20% (7% to 31%)	57% (44% to 67%) ‐	51% (27% to 67%) ‐	−33%^d (−80% to 1%) ‐
O'Brien 2008^a,c	‐	64% (−34% to 90%)	‐	‐	‐	‐	‐	‐
*OMPC‐PCV7*
Kilpi 2003	‐	‐	‐	‐	25% (11% to 37%)	56% (44% to 66%)	−5%^d (−47% to 25%)	−27%^d (−70% to 6%)
*PHiD‐PC10 and PHiD‐PC11*
Tregnaghi 2014 Sáez‐Llorens 2017	53% (16% to 74%)	70% (30% to 87%)	29% (−123% to 77%)	15% (−153% to 71%)	56% (13% to 78%)	67% (17% to 87%)	26% (−232% to 83%)	26% (−231% to 83%)
Vesikari 2016^c	‐	‐	‐	‐	‐	‐	‐	‐
Prymula 2006	‐	‐	‐	‐	52% (37% to 63%)	58% (41% to 69%)	66% (22% to 85%)	9% (−64% to 49%)
PCV administered at a later age
*CRM197‐PCV7 followed by PPV23*
Veenhoven 2003	‐	‐	‐	‐	34% P = 0.22	52% P = 0.21	‐	21% P = 0.44
van Kempen 2006	‐	‐	‐	‐	‐	‐	‐	‐
*CRM197‐PCV7/TIV*
Jansen 2008	‐	‐	‐	‐	‐	‐	‐	‐
*CRM197‐PCV9*
Dagan 2001	‐	‐	‐	‐	‐	‐	‐	‐

AOM: acute otitis media
CI: confidence interval
CRM197‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197
CRM197‐PCV7/TIV: trivalent influenza vaccine plus 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197
CRM197‐PCV9: 9‐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
PPV23: 23‐valent pneumococcal polysaccharide vaccine
TIV: trivalent influenza vaccine
VE: vaccine efficacy
^aMiddle ear fluid collected from spontaneous draining ears; in the other studies middle ear fluid was routinely collected during AOM episodes through paracentesis.
^bAdditional analysis of Eskola 2001 including pneumococcal AOM by a positive culture or polymerase chain reaction (PCR).
^cCluster‐randomised controlled trial.
^dnegative values represent an increase in the risk of AOM.

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Table 3. Effect of pneumococcal conjugate vaccination on frequency of recurrent acute otitis media

	VE expressed as relative reduction in risk (95% CI)	VE expressed as relative reduction in risk (95% CI)
	Intention‐to‐treat	Per‐protocol
PCV administered in infancy
CRM197‐PCV7
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%)
O'Brien 2008^a	‐	‐
OMPC‐PCV7
Kilpi 2003	‐	‐
PHiD‐PC10 and PHiD‐PC11
Tregnaghi 2014 Sáez‐Llorens 2017	‐	‐
Vesikari 2016^a	‐	‐
Prymula 2006	‐	56% (−2% to 81%)
PCV administered at a later age
CRM197‐PCV7 followed by PPV23
Veenhoven 2003	‐	‐
van Kempen 2006	‐	‐
CRM197‐PCV7/TIV
Jansen 2008	‐	‐
CRM197‐PCV9
Dagan 2001	‐	‐

CI: confidence interval
CRM197‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197
CRM197‐PCV7/TIV: trivalent influenza vaccine plus 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197
CRM197‐PCV9: 9‐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
PPV23: 23‐valent pneumococcal polysaccharide vaccine
TIV: trivalent influenza vaccine
VE: vaccine efficacy
^aCluster‐randomised controlled trial

We included a total of 15 publications of 11 RCTs (60,733 children, range 74 to 37,868 per trial) of 7‐ to 11‐valent PCVs versus control vaccines. Seven trials included infants who predominantly received primary vaccinations before six months of age (59,415 children in total) (Black 2000/Fireman 2003; Eskola 2001/Palmu 2009; Kilpi 2003; O'Brien 2008; Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017; Vesikari 2016/Karppinen 2019). One study included daycare attendees aged 12 to 35 months (264 children) (Dagan 2001). Two trials included children aged one to seven years with a history of AOM (457 children) (van Kempen 2006; Veenhoven 2003). One trial included children aged 18 to 72 months with a previously diagnosed RTI (597 children) (Jansen 2008).

We have presented the results of individual trials as reported in the published papers; meta‐analysis was inappropriate due to substantial differences amongst studies. We have assessed the statistical methods used to analyse data in each study.

Adverse effects (co‐primary outcome)

An overview of adverse effects reported in the individual studies can be found in Table 4.

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Table 4. Adverse effects

Study ID	No. of participants	PCV type	Redness	Swelling	Pain/tenderness	Fever	Serious adverse events
Black 2000/Fireman 2003	37,868	CRM197‐PCV7	Depending on timing of dose, redness occurred in around 10% to 14% of children receiving CRM197‐PCV7 versus 5% to 9% of children receiving MenC vaccination. More severe redness (> 3 cm) occurred in 0% to 0.6% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and MenC groups.	Depending on timing of dose, swelling occurred in around 10% to 12% of children receiving CRM197‐PCV7 versus 3% to 8% of children receiving MenC vaccination. More severe swelling (> 3 cm) occurred in 0.1% to 0.6% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and MenC groups.	Depending on timing of dose, tenderness was reported in 15% to 23% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and MenC groups.	Depending on timing of dose, fever > 38 °C occurred in around 15% to 24% of children receiving CRM197‐PCV7 versus 9% to 17% of children receiving MenC vaccination. Fever (> 39 °C) occurred in 0.9% to 2.5% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and MenC groups.	No severe adverse events related to vaccination resulting in hospitalisation, emergency, or clinic visits were reported.
Dagan 2001	264	CRM197‐PCV9	Depending on timing of dose, redness occurred in 5% to 6% of children receiving CRM197‐PCV9 versus 0% to 5% of children receiving MenC vaccination.	Depending on timing of dose, swelling occurred in 7% to 12% of children receiving CRM197‐PCV9 versus 0% to 5% of children receiving MenC vaccination.	Depending on timing of dose, tenderness was reported in 25% to 38% of children receiving CRM197‐PCV9 versus 0% to 8% of children receiving MenC vaccination.	Depending on timing of dose, fever > 38 °C occurred in around 15% to 44% of children receiving CRM197‐PCV9 versus 8% to 25% of children receiving MenC vaccination. Fever (> 39.5 °C) occurred in only 1 child receiving CRM197‐PCV9 versus 3 children receiving MenC vaccination.	Not reported
Eskola 2001/Palmu 2009	1662	CRM197‐PCV7	Depending on timing of dose, redness occurred in 14% to 20% of children receiving CRM197‐PCV7 versus 9% to 16% of children receiving hepatitis vaccines. More severe redness (> 2.5 cm) occurred in 0% to 0.9% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and hepatitis vaccine groups.	Depending on timing of dose, swelling occurred in 5% to 6% of children receiving CRM197‐PCV7 versus 2% to 6% of children receiving hepatitis vaccines. More severe swelling (> 2.5 cm) occurred in 0.5% to 1.3% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and hepatitis vaccine groups.	Depending on timing of dose, pain was reported in 3% to 8% of children receiving CRM197‐PCV7 versus 2% to 3% of children receiving hepatitis vaccines.	Fever (> 39 °C) occurred in 0.4% to 2.0% of children receiving CRM197‐PCV7 versus 0.2% to 1.7% of children receiving hepatitis vaccines.	No significant differences between vaccine groups were observed for unexpected events (6 versus 4 events). 1 child in the CRM197‐PCV7 group died from bowel obstruction, necrosis, and shock at the age of 8 months (85 days after administration of third dose), but death was assessed as unrelated to study vaccine (autopsy revealed mesenteric defects with volvulus and other congenital abnormalities).
Jansen 2008	579	CRM197‐PCV7/TIV	‐	‐	‐	‐	Quote: “In general, the vaccinations were well‐tolerated, and no immediate or severe adverse events were recorded.”
Kilpi 2003	1666	OMPC‐PCV7	OMPC‐PCV7 caused local reactions within 3 days of each dose more often than the hepB vaccine (data not shown).	OMPC‐PCV7 caused local reactions within 3 days of each dose more often than the hepB vaccine (data not shown).	Not reported	Not reported	There were no statistically significant differences in the occurrence of any diagnosis among individuals who experienced serious adverse events between the 2 vaccine groups. 1 child in the OMPC‐PCV7 group died from volvulus due to bowel obstruction. Death was assessed as unrelated to study vaccine.
Prymula 2006	4968	PHiD‐CV11	Not reported	Not reported	Not reported	Not reported	The percentages of infants with unsolicited symptoms that were judged to be causally related to vaccination were similar in the PHiD‐CV11 and hepA groups (2.5% versus 3.0%). 14 serious adverse events were judged to be causally related to vaccination: 8 occurred in children receiving PHiD‐CV11 vaccination (7 after co‐administration with Infanrix hexa and 1 after PHiD‐CV11 booster) versus 6 in children receiving hepatitis A control vaccine (7 after co‐administration with Infanrix hexa and 1 after hepatitis A booster with Infanrix hexa). All events, apart from 1 case of epilepsy in the hepatitis A group, resolved without sequelae. 4 children died during the study, 1 in the PHiD‐CV11 group (8 months after third dose, diagnosis of epilepsy was made; 25 months after the third dose the child had grand mal epilepsy and died from suffocation). None of the deaths were regarded by the investigators as related to the study vaccine.
Tregnaghi 2014/Sáez‐Llorens 2017	23,821	PHiD‐CV10	Not reported	Not reported	Not reported	Not reported	Serious adverse events did not differ significantly between PHiD‐CV10 and hepatitis control vaccines (21.5% versus 22.6%). Only 1 event (in the control group) was judged to be causally related to vaccination by the investigator, and it resolved without sequelae. 19 children died in the PHiD‐CV10 group (0.16%) versus 26 in the control group (0.22%). None of the deaths were considered by the investigator to be causally related to vaccination.
Veenhoven 2003	383	CRM197‐PCV7	Not reported	Not reported	Not reported	Not reported	No serious adverse events were noted after administration of CRM197‐PCV7 or hepatitis control vaccines.
Vesikari 2016	6178	PHiD‐CV10	Not reported	Not reported	Not reported	Not reported	Serious adverse events considered by the investigator to be causally related to vaccination were reported in 4 infants in the PHiD‐CV10 group (all in 3 + 1 group: sepsis with non‐specified aetiology in 1 infant, pyrexia in 1 infant, convulsion in 2 infants) and in 2 infants in hepB group (petit mal epilepsy in 1 infant and pyrexia in 1 infant). 1 fatal serious adverse event (sudden infant death, not considered to be vaccination related) was reported in the PHiD‐CV10 (2 + 1) group.

CRM197‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197
CRM197‐PCV7/TIV: trivalent influenza vaccine plus 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197
CRM197‐PCV9: 9‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197
hepA: hepatitis A
hepB: hepatitis B
MenC: meningococcus type C
OMPC‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to the outer membrane protein complex of Neisseria meningitidis serogroup B
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)
TIV: trivalent influenza vaccine

Mild local reactions and fever were common in both groups, occurring 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 or tenderness, or both, was reported more frequently in children receiving PCV than in those receiving control vaccines: 3% to 38% versus 0% to 8%. Serious adverse events (SAEs) judged to be causally related to vaccination were rare and did not differ significantly between vaccine groups. No fatal SAE judged to be causally related to vaccination was reported.

The certainty of evidence for this outcome was high.

Acute otitis media outcomes (co‐primary outcome and secondary outcomes)

Seven studies used the generalised Cox proportional hazard method proposed by Andersen 1982, currently regarded as the most optimal for analysing this kind of data (Black 2000/Fireman 2003; Eskola 2001/Palmu 2009; Kilpi 2003; Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017; van Kempen 2006; Veenhoven 2003).

Dagan 2001 compared rates of AOM, but rather than comparing them by Poisson or negative binomial regression analysis (which would presumably yield results similar to those obtained with the Andersen approach), the Chi² test was used, which is suboptimal for comparing rates.

Jansen 2008 used Poisson, and Vesikari 2016/Karppinen 2019 used negative binomial regression analysis to compare rates of AOM between groups, accounting for the potential dependency of observations between individuals.

O'Brien 2008 was a cluster‐RCT that calculated incidence rate ratios with a Poisson regression with sandwich variance estimation to account for within‐community correlation.

Effect of PCV administered in early infancy (predominantly < 6 months of age)

Seven trials (59,415 children) included infants who predominantly received various types of PCV before six months of age (Black 2000/Fireman 2003; Eskola 2001/Palmu 2009; Kilpi 2003; O'Brien 2008; Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017; Vesikari 2016/Karppinen 2019).

PCV7

In two trials (39,530 children), CRM197‐PCV7 was the intervention for healthy infants aged two months (Black 2000/Fireman 2003; Eskola 2001/Palmu 2009). The same vaccine was used as the intervention in one trial including 944 Navajo and White Mountain Apache children aged up to two years. These children carry one of the highest risks of developing AOM in the world (O'Brien 2008).

In one trial (1666 children), OMPC‐PCV7, with a subset of children receiving PPV23 as a booster dose, was used as the intervention in healthy infants aged two months (Kilpi 2003).

Primary outcome

Frequency of all‐cause AOM episodes

In one trial including 37,868 healthy infants aged two months, CRM197‐PCV7 was associated with a 6% (95% confidence interval (CI) 4% to 9%) relative risk reduction (RRR) in all‐cause AOM episodes in an intention‐to‐treat (ITT) analysis (Black 2000/Fireman 2003). Per‐protocol analysis of a trial including 1662 healthy infants aged two months showed that this same vaccine was associated with a non‐significant 6% (95% CI −4% to 16%) RRR in all‐cause AOM episodes (Eskola 2001/Palmu 2009).

In young children who carry a high baseline risk of developing AOM, CRM197‐PCV7 was not associated with a reduction in all‐cause AOM episodes (1 trial; 944 children; RRR −5%, 95% CI −25% to 12%; ITT analysis) (O'Brien 2008).

In one trial including 1666 healthy infants aged two months, OMPC‐PCV7 was not associated with a reduction in all‐cause AOM episodes in per‐protocol analysis (RRR −1%, 95% CI −12% to 10%) (Kilpi 2003).

The certainty of evidence for the use of CRM197‐PCV7 in low‐risk infants for this outcome was moderate, downgraded one level due to imprecise effect estimate and study limitations (risk of bias). The certainty of evidence for the use of CRM197‐PCV7 in young children with a high baseline risk of developing AOM and the use of OMPC‐PCV7 in low‐risk infants for this outcome was low; in both cases, the certainty of evidence was downgraded two levels due to the very imprecise effect estimate.

Secondary outcomes

Frequency of pneumococcal AOM

In one trial including 1662 healthy infants aged two months, CRM197‐PCV7 was associated with a 20% (95% CI 7% to 31%) to 34% (95% CI 21% to 45%) RRR in pneumococcal AOM episodes in per‐protocol analysis, depending on whether this outcome was assessed by a composite of positive culture or positive pneumolysin polymerase chain reaction (PCR) or by positive culture only (Eskola 2001/Palmu 2009).

In one trial including 1666 healthy infants aged two months, OMPC‐PCV7 was associated with a 25% (95% CI 11% to 37%) RRR in pneumococcal AOM episodes in per‐protocol analysis (Kilpi 2003).

The certainty of evidence for this outcome was high.

Frequency of pneumococcal serotype‐specific AOM

In two trials (39,530 healthy infants aged two months), administration of CRM197‐PCV7 was associated with a 54% (95% CI 41% to 64%) to 65% (P = 0.04) RRR in vaccine‐type pneumococcal AOM episodes in ITT analysis (Black 2000/Fireman 2003; Eskola 2001/Palmu 2009).

In one of these trials, CRM197‐PCV7 was associated with a 51% (95% CI 27% to 67%) RRR in AOM episodes caused by cross‐reactive serotypes and a non‐significant 33% (95% CI −80% to 1%) relative increase in the risk of non‐vaccine‐type AOM episodes in per‐protocol analyses (Eskola 2001/Palmu 2009).

In one trial (944 children), administration of CRM197‐PCV7 in young children who carried a high baseline risk of developing AOM was associated with a non‐significant 64% (95% CI −34% to 90%) RRR in vaccine‐type pneumococcal AOM episodes in ITT analysis (O'Brien 2008).

In one trial including 1666 healthy infants aged two months, OMPC‐PCV7 was associated with a 56% (95% CI 44% to 66%) RRR in vaccine‐type pneumococcal AOM episodes in per‐protocol analysis (Kilpi 2003). In the same trial, OMPC‐PCV7 failed to show cross‐protection (RRR −5%, 95% CI −47% to 25%), and this vaccine was associated with a non‐significant 27% (95% CI −70% to 6%) relative increase in the risk of non‐vaccine‐type AOM episodes in per‐protocol analyses (Kilpi 2003).

The certainty of evidence for the use of CRM197‐PCV7 and OMPC‐PCV7 in healthy infants for this outcome was high. However, the certainty of evidence for the use of CRM197‐PCV7 in young children with high baseline risk of developing AOM for this outcome was moderate, downgraded one level due to study limitations (risk of bias) and imprecise effect estimate.

Frequency of recurrent AOM

In two trials (39,530 children), administration of CRM197‐PCV7 in healthy infants aged two months was associated with a 9% (95% CI −12% to 27%) to 10% (95% CI 7% to 13%) RRR in developing recurrent AOM (Black 2000/Fireman 2003; Eskola 2001/Palmu 2009).

The certainty of evidence for this outcome was moderate, downgraded one level due to imprecise effect estimate.

PHiD‐CV10/11

PHiD‐CV10 was used as the intervention in two trials (12,307 children) (Tregnaghi 2014/Sáez‐Llorens 2017; Vesikari 2016/Karppinen 2019). PHiD‐CV11 was used in one trial (4968 children) (Prymula 2006).

Primary outcome

Frequency of all‐cause AOM episodes

In one trial including 7359 healthy infants aged 6 to 16 weeks, PHiD‐CV10 was associated with a non‐significant 15% (95% CI −1% to 28%) RRR in all‐cause AOM episodes in ITT analysis (Tregnaghi 2014/Sáez‐Llorens 2017). Per‐protocol analysis of a trial including 5095 healthy infants aged 6 weeks to 18 months showed that this same vaccine was associated with a non‐significant 6% (95% CI −6% to 17%) RRR in all‐cause AOM episodes (Vesikari 2016). In Karppinen 2019, a subcohort of 424 children nested within the FinIP trial, PHiD‐CV10 was associated with a significant 23% (95% CI 0% to 40%) RRR in all‐cause episodes of respiratory tract infections with AOM in per‐protocol analysis.

In one trial including 4968 healthy infants aged 6 weeks to 5 months, PHiD‐CV11 was associated with a 34% (95% CI 21% to 44%) RRR in all‐cause AOM episodes in per‐protocol analysis (Prymula 2006).

However, it should be noted that the AOM incidence rates in the two trials with the largest point estimates, Prymula 2006; Tregnaghi 2014/Sáez‐Llorens 2017, were low (Table 1). Consequently, the absolute risk differences in these trials were rather small.

The certainty of evidence for the use of PHiD‐CV10 for this outcome was low, downgraded two levels due to study limitations (risk of bias) and imprecise effect estimates. The certainty of evidence for the use of PHiD‐CV11 for this outcome was moderate, downgraded one level due to indirectness of evidence (low AOM incidence rate in the control group compared to other studies, most likely due to methodological differences with other studies).

Secondary outcomes

Frequency of pneumococcal AOM

In one trial including 7359 healthy infants aged 6 to 16 weeks, PHiD‐CV10 was associated with a 53% (95% CI 16% to 74%) RRR in pneumococcal AOM episodes in ITT analysis (Tregnaghi 2014/Sáez‐Llorens 2017).

In one trial including 4968 healthy infants aged 6 weeks to 5 months, PHiD‐CV11 was associated with a 52% (95% CI 37% to 63%) RRR in pneumococcal AOM episodes in per‐protocol analysis (Prymula 2006).

The certainty of evidence for pneumococcal AOM episodes was high.

Frequency of pneumococcal serotype‐specific AOM

In one trial including 7359 healthy infants aged 6 to 16 weeks, PHiD‐CV10 was associated with a 70% (95% CI 30% to 87%) RRR in vaccine‐type pneumococcal AOM episodes in ITT analysis (Tregnaghi 2014/Sáez‐Llorens 2017). In the same trial, PHiD‐CV10 was associated with a non‐significant 29% (95% CI −123% to 77%) RRR in AOM episodes caused by cross‐reactive serotypes and a non‐significant 15% (95% CI −153% to 71%) RRR in non‐vaccine‐type AOM episodes in ITT analyses (Tregnaghi 2014/Sáez‐Llorens 2017).

In one trial including 4968 healthy infants aged 6 weeks to 5 months, PHiD‐CV11 was associated with a 58% (95% CI 41% to 69%) RRR in vaccine‐type pneumococcal AOM episodes in per‐protocol analysis (Prymula 2006). In the same trial, PHiD‐CV11 was associated with a 66% (95% CI 22% to 85%) RRR in AOM episodes caused by cross‐reactive serotypes and a non‐significant 9% (95% CI −64% to 49%) RRR in non‐vaccine‐type AOM episodes in per‐protocol analyses (Prymula 2006).

The certainty of evidence for vaccine‐type pneumococcal AOM episodes was high. The certainty of evidence for cross‐reactive serotypes and non‐vaccine‐type AOM episodes was low, downgraded two levels due to very imprecise effect estimates.

Frequency of recurrent AOM

In one trial including 4968 healthy infants aged 6 weeks to 5 months, PHiD‐CV11 was associated with a non‐significant 56% (95% CI −2% to 80%) RRR in developing recurrent AOM in per‐protocol analysis (Prymula 2006).

The certainty of evidence for this outcome was low, downgraded two levels due to imprecise effect estimate and indirectness of evidence (low AOM incidence rate in control group compared to other studies, most likely due to methodological differences with other studies).

Effect of PCV administered at a later age (one year and above)

In three trials, various types of PCV7 were administered in children with a history of either RTI (597 participants), Jansen 2008, or AOM (457 participants in total) (van Kempen 2006; Veenhoven 2003).

CRM197‐PCV7

Primary outcome

Frequency of all‐cause AOM episodes

In two trials (457 children) (van Kempen 2006; Veenhoven 2003), CRM197‐PCV7 followed by PPV23 in children aged one to seven years with a history of AOM was not associated with further reductions in AOM episodes (1 trial; 383 children; RRR −25%, 95% CI −57% to 1%; ITT analysis (Veenhoven 2003); 1 trial; 74 children; RRR −16%, 95% CI −96% to 31%; per‐protocol analysis (van Kempen 2006)).

In one trial including 597 children with a history of RTI, CRM197‐PCV7 administered together with a trivalent influenza vaccine (CRM197‐PCV7/TIV) was associated a 57% (95% CI 6% to 80%) RRR in all‐cause AOM episodes compared to hepatitis B/placebo vaccination in per‐protocol analysis (Jansen 2008). However, the effect of TIV/placebo compared to hepatitis B/placebo vaccination on all‐cause AOM episodes appeared to be even larger (RRR 71%, 95% CI 30% to 88%) (Jansen 2008).

The certainty of evidence for this outcome was moderate, downgraded one level due to imprecise effect estimates.

Secondary outcomes

Frequency of pneumococcal AOM

In per‐protocol analysis of one trial including 383 children with a history of AOM, CRM197‐PCV7 followed by PPV23 was associated with a non‐significant 34% (P = 0.22) RRR in pneumococcal AOM episodes (Veenhoven 2003).

The certainty of evidence for this outcome was low, downgraded two levels due to very imprecise effect estimates (one study with a relatively small sample size).

Frequency of pneumococcal serotype‐specific AOM

In a per‐protocol analysis of one trial including 383 children with a history of AOM, CRM197‐PCV7 followed by PPV23 was associated with a non‐significant 52% (P = 0.21) and 21% (P = 0.21) RRR in pneumococcal serotype‐specific AOM and non‐vaccine‐type AOM episodes (Veenhoven 2003).

The certainty of evidence for this outcome was low, downgraded two levels due to very imprecise effect estimates (one study with a relatively small sample size).

Frequency of recurrent AOM

None of the three trials in older children reported the effect of PCV7 on recurrent AOM.

CRM197‐PCV9

In one trial (264 children), CRM197‐PCV9 was administered in healthy daycare attendees aged 12 to 35 months (Dagan 2001).

Primary outcome

Frequency of all‐cause AOM episodes

In a per‐protocol analysis, CRM197‐PCV9 was associated with a non‐significant 17% (95% CI −2% to 33%) RRR in all‐cause otitis (OM) episodes (Dagan 2001).

The certainty of evidence for this outcome was very low, downgraded three levels due to study limitations (risk of bias and questions about outcome assessment) and imprecise effect estimate (one study with a relatively small sample size).

Secondary outcomes

Dagan 2001 did not report on any of our secondary outcomes of interest.

Discussion

Summary of main results

The current evidence base for the effects of PCVs in preventing AOM in children comes from 11 RCTs (60,733 children) of 7‐ to 11‐valent PCVs versus control vaccines (meningococcus type C conjugate vaccine in three trials and hepatitis A or B vaccine in eight trials) with a generally low risk of bias. No relevant RCTs with the newer 13‐valent PCV were available. In seven trials (59,415 children), PCVs were predominantly administered in child's first months of life, whilst four trials (1318 children) included children aged one year and over who were either healthy or who had a history of respiratory illness. There was considerable clinical heterogeneity across studies in terms of design, study population, type of PCV used, and outcome measures, therefore we did not perform meta‐analyses.

The licenced CRM197‐PCV7 and PHiD‐CV10 vaccines, when administered during early infancy (< 6 months of age), were associated with substantial RRR in pneumococcal AOM (high‐certainty evidence). However, their effects on all‐cause AOM are far more uncertain, as most trials failed to demonstrate statistically significant differences for this outcome. Relative risk reductions for CRM197‐PCV7 varied from −5% (95% CI −25% to 12%) in high‐risk infants (low‐certainty evidence) to 6% (95% CI −4% to 16%) and 6% (95% CI 4% to 9%) in low‐risk infants (moderate‐certainty evidence), whereas RRRs for PHiD‐CV10 varied from 6% (95% CI −6% to 17%) to 15% (95% CI −1% to 28%) in healthy infants (low‐certainty evidence).

Administration of PCVs in high‐risk infants, after early infancy, and in older children with a history of respiratory illness or frequent AOM was not associated with reductions in all‐cause AOM.

Local redness, swelling, fever, and tenderness/pain were commonly reported and occurred more frequently in children receiving PCV than in those receiving control vaccines, but these adverse effects were mostly mild. More severe redness (> 2.5 cm), swelling (> 2.5 cm), and fever (> 39 °C) occurred far less frequently and did not differ between vaccine groups. Serious adverse events judged to be causally related to vaccination were rare and did not differ significantly between vaccine groups. No fatal SAE judged to be causally related to vaccination was reported.

Overall completeness and applicability of evidence

The 11 RCTs included in this review differed substantially in terms of RCT type, study population (age of PCV administration and AOM baseline risk), PCV type (vaccine valency, carrier protein, and booster regimen), co‐administration of other vaccines, and AOM assessment and definition used. Furthermore, in the infant studies focusing on AOM bacteriology (Eskola 2001; Kilpi 2003; Prymula 2006; Tregnaghi 2014), the control groups varied markedly in the proportions of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis found in the middle ear fluid. This might be related to time and geographic region as well as case definition, and has important implications for the effects of PCV on preventing all‐cause AOM episodes. Additionally, three studies included older otitis‐prone children, so the intervention was aimed at secondary or even tertiary prevention, and not primary prevention (Jansen 2008; van Kempen 2006; Veenhoven 2003). The reduced efficacy of CRM197‐PCV7 in children with a history of AOM may be explained by an increased susceptibility to subsequent infections, not only with non‐vaccine‐type pneumococci, but also other nasopharyngeal colonisers, due to 'damage' already suffered by the middle ear mucosa caused by prior AOM (Veenhoven 2003). Another explanation, whilst debated, could be the non‐protective, impaired antibody responses of children who are otitis‐prone (Pichichero 2013; Wiertsema 2012). It thus appears that the age at which PCV is administered, a history of AOM episodes, or both, modifies the effect of PCV on AOM, despite the fact that age alone could not be identified as a statistically significant effect modifier (Black 2000/Fireman 2003; Veenhoven 2003). Our review did not focus on the effects of PCVs on shifts in serotypes over time. Further research into the impact of PCVs on (serotype) replacement is warranted, since a shift in causative pathogens may have considerable implications for both AOM burden and vaccine effectiveness.

Quality of the evidence

The certainty of evidence varied substantially per outcome measure. For the frequency of all‐cause AOM and recurrent AOM, the certainty of evidence varied from moderate (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) to low (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). The certainty of evidence for adverse effects and frequency of pneumococcal AOM was high (further research is very unlikely to change our confidence in the estimate of effect).

Potential biases in the review process

We adhered to the prespecified review protocol. Two review authors (JLHdS, RPV for the 2020 update) independently searched all relevant electronic databases using a search syntax comprising all relevant synonyms for PCV and AOM. We also performed a broad internet search to identify potentially relevant articles. To increase the yield of relevant studies, we reviewed the reference lists of all identified studies and systematic reviews or meta‐analyses. We searched ClinicalTrials.gov and the WHO ICTRP for completed and ongoing trials. For the 2020 update, a new review author (JLHdS) independently reviewed 'Risk of bias' and GRADE assessments and data extraction of all included studies. Any discrepancies with the findings described in the 2019 update were discussed with a second review author (RPV), and where needed, with a third review author (RAMJD).

Agreements and disagreements with other studies or reviews

Our main findings are in agreement with three other systematic reviews on the effect of PCV in children, indicating that PCVs provide substantial protection against pneumococcal AOM, but that their effects on all‐cause AOM are more uncertain and far less pronounced (Ewald 2016; Pavia 2009; Taylor 2012).

In AOM, there is a high potential for replacement by other bacterial pathogens that are common colonisers of the nasopharynx. CRM197‐PCV7 is known to affect nasopharyngeal carriage of pneumococci, with a shift from vaccine‐type pneumococci to non‐vaccine‐type pneumococci and other otopathogens including non‐typeable H influenza and Staphylococcus aureus (Biesbroek 2014; Block 2006; Casey 2013; Coker 2010; Eskola 2001; Obaro 1996; Somech 2011; van Gils 2011; Wiertsema 2011). Nasopharyngeal carriage results from a recent RCT on PHiD‐CV10 showed similar bacterial colonisation patterns as observed in CRM197‐PCV7 amongst healthy Dutch children aged up to two years (van den Bergh 2013). The middle ear is directly connected to the nasopharynx, and by lowering the carriage of vaccine‐type pneumococci, a niche may be created for other bacteria with pathogenic potential (Block 2006; Veenhoven 2003; Veenhoven 2004). Recent studies have shown that nationwide implementation of PCVs may have changed the frequency of the causative otopathogens involved in AOM towards pneumococcal serotypes not included in the vaccines and non‐typeable H influenzae (Ben‐Shimol 2019; Casey 2013; Coker 2010; Kaur 2017; Somech 2011; Wiertsema 2011).

Although RCT data failed to demonstrate a convincing beneficial effect of CRM197‐PCV7 and PHiD‐CV10 on all‐cause AOM, various global postmarketing studies with these licenced vaccines, as well as the newer CRM197‐PCV13, suggest that the impact of PCVs on AOM may be substantial (Eythorsson 2018; Gisselsson‐Solen 2017; Kawai 2018; Lau 2015; Lecrenier 2020; Magnus 2012; Marom 2014; Poehling 2007; Sigurðsson 2018; Soysal 2020; Zhou 2008), which may be attributable to indirect (herd) effects of vaccination. However, it should be noted that findings from observational studies warrant careful interpretation, as variability in baseline incidence, study population, and case definition, as well as fluctuations in risk factors for AOM such as breastfeeding, household smoking, daycare attendance rates, and implementation of AOM clinical practice guidelines, may affect the AOM incidences reported. For example, results from Boston (USA) showed that the decline in uncomplicated AOM, treatment failure, and AOM relapse was at least as large in the 2000‐to‐2004 period compared to the 1996‐to‐2000 period, leaving the 'true' contribution of PCV in reducing AOM incidence uncertain (Sox 2008). Furthermore, reduced exposure to household smoking amongst other factors such as PCV7 coverage since 2002, may have contributed to the steady decline in USA paediatric ambulatory visits for otitis media over the period of 1993 to 2006 (Alpert 2011).

The impact of PHiD‐CVs may expand beyond their effects on pneumococcal AOM to AOM caused by non‐typeable H influenzae due to the carrier protein D (Forsgren 2008). A recent review including pre‐clinical, clinical, and postmarketing studies concluded that PHiD‐CVs may decrease AOM caused by non‐typeable H influenzae, but that more evidence including pathogen‐specific outcomes is clearly warranted (Clarke 2017). The diversity of non‐typeable H influenzae, with some strains lacking protein D, may limit the effect of PHiD‐CVs on non‐typeable H influenzae AOM. In our review, administration of the licenced PHiD‐CV10 in healthy infants was associated with non‐significant 6% (95% CI −6% to 17%) and 15% (95% CI −1% to 28%) relative reductions in the risk of all‐cause AOM. The added benefit of PHiD‐CV10 over the previously licenced CRM197‐PCV7 on all‐cause AOM therefore remains uncertain.

We found limited evidence that administration of PCVs during infancy may reduce the risk of recurrent AOM. This is in line with accumulating evidence that PCVs might disrupt the continuum of evolution from pneumococcal‐associated otitis media towards chronic/recurrent otitis media by prevention of early vaccine‐serotype AOM, thereby reducing subsequent and more complex disease caused by non‐vaccine serotypes and non‐typeable H influenzae (Ben‐Shimol 2014; Dagan 2016). These findings are further supported by secondary analyses of some of the trials included in our review indicating that licenced CRM197‐PCV7 and PHiD‐PCV10 lead to fewer ventilation tubes insertions for chronic/recurrent otitis media (Black 2000; Palmu 2015b; Sarasoja 2013).

Figure 1

Study flow diagram.

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Figure 2

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

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Figure 3

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

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Summary of findings 1. Pneumococcal conjugate vaccine versus control vaccine for preventing acute otitis media in children

PCV type	VE ‐ relative effect (95% CI)*	No. of participants (studies)	Certainty of evidence	Comments
Pneumococcal conjugate vaccine versus control vaccine for preventing acute otitis media in children
Patient or population: infants (predominantly < 6 months of age) and older children (aged 1 to 7 years) Settings: community (Finland, the Netherlands, the Czech Republic and Slovakia, Israel, the USA, Argentina, Colombia, and Panama) Intervention: multivalent PCVs Comparison: control vaccine
Frequency of all‐cause acute otitis media
CRM197‐PCV7in low‐risk infants	RRR: 6% (−4% to 16%) to 6% (4% to 9%)^#	39,530 (2 RCTs)	⊕⊕⊕⊝ Moderate^a	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.
CRM197‐PCV7in high‐risk infants	RRR: −5% (−25% to 12%)	944 (1 RCT)	⊕⊕⊝⊝ Low^b	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 RCT)	⊕⊕⊝⊝ Low^b	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 RCTs)	⊕⊕⊝⊝ Low^c	Results are derived from 2 trials with low, Tregnaghi 2014/Sáez‐Llorens 2017, and unclear risk of bias (Vesikari 2016/Karppinen 2019). AOM incidence rate in the control group of 1 trial, Tregnaghi 2014/Sáez‐Llorens 2017, was low compared to other studies (Table 1).
PHiD‐CV11in low‐risk infants	RRR: 34% (21% to 44%)	4968 (1 RCT)	⊕⊕⊕⊝ Moderate^d	Results are derived from 1 trial with low risk of bias (Prymula 2006). AOM incidence rate in the control group was low compared to other studies (Table 1).
Adverse effects
CRM197‐PCV7in low‐risk infants OMPC‐PCV7in low‐risk infants PHiD‐PC10 and PHiD‐PC11 in low‐risk infants CRM197‐PCV7/9 and CRM197‐PCV7 plus TIVin older children	Mild local reactions and fever were common in both groups, occurring 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 to be causally related to vaccination were rare and did not differ significantly between vaccine groups. No fatal serious adverse event judged to be causally related to vaccination was reported.	77,389 (9 RCTs)	⊕⊕⊕⊕ High	Results are derived from 9 trials with low risk of bias.
Frequency of pneumococcal acute otitis media
CRM197‐PCV7in low‐risk infants	RRR: 20% (7% to 31) to 34% (21% to 45%)	1662 (1 RCT)	⊕⊕⊕⊕ 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 RCT)	⊕⊕⊕⊕ 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 RCT)	⊕⊕⊕⊕ 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 RCT)	⊕⊕⊕⊕ High	Results are derived from 1 trial with low risk of bias (Prymula 2006).
Frequency of recurrent acute otitis media (defined as 3 or more acute otitis media 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 RCTs)	⊕⊕⊕⊝ Moderate^e	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, both with low risk of bias.
PHiD‐CV11in low‐risk infants	RRR: 56% (−2% to 80%)	4968 (1 RCT)	⊕⊕⊝⊝ Low^f	Results are derived from 1 trial with low risk of bias (Prymula 2006).
*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 and positive pneumolysin polymerase chain reaction (PCR) or by positive culture only, or whether ITT or per‐protocol analysis was performed.
GRADE (certainty in the evidence) High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: 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 certainty: Any estimate of effect is very uncertain.
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) RCT: randomised controlled trial RRR: relative risk reduction TIV: trivalent influenza vaccine VE: vaccine efficacy ^aWe downgraded the certainty of the evidence from high to moderate due to imprecise effect estimate and study limitations (risk of bias). ^bWe downgraded the certainty of the evidence from high to low due to the very imprecise effect estimate. ^cWe downgraded the certainty of the evidence from high to low due to study limitations (risk of bias) and imprecise effect estimates. ^dWe downgraded the certainty of the evidence from high to moderate due to indirectness of evidence (low AOM incidence rate in the control group compared to other studies, most likely due to methodological differences with other studies). ^eWe downgraded the certainty of the evidence from high to moderate due to imprecise effect estimate. ^fWe downgraded the certainty of the evidence from high to low due to imprecise effect estimate and indirectness of evidence (low AOM incidence rate in the control group compared to other studies, most likely due to methodological differences with other studies).

Summary of findings 1. Pneumococcal conjugate vaccine versus control vaccine for preventing acute otitis media in children

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Table 1. Effect of pneumococcal conjugate vaccination on frequency of all‐cause acute otitis media episodes

	Episodes/person‐year		Incidence rate difference ‐ episodes per person‐year (95% CI)	VE expressed as relative reduction in risk (95% CI)^a	Episodes/person‐year		Incidence rate difference ‐ episodes per person‐year (95% CI)	VE expressed as relative reduction in risk (95% CI)^a
	Intention‐to‐treat				Per‐protocol
	Treatment	Control		VE expressed as relative reduction in risk (95% CI)^a	Treatment	Control		VE expressed as relative reduction in risk (95% CI)^a
PCV administered in early infancy
*CRM197‐PCV7*
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^d	6% (−4% to 16%)
O'Brien 2008^b	1.43	1.36	0.07 (−0.05 to 0.18)	−5% (−25% to 12%)^c	1.35	1.35	0.00 (−0.13 to 0.14)	0% (−21% to 17%)
*OMPC‐PCV7*
Kilpi 2003	‐	‐	‐	‐	‐	‐	‐	−1%^h (−12% to 10%)
*PHiD‐PC10 and PHiD‐PC11*
Tregnaghi 2014 Sáez‐Llorens 2017	0.03	0.04	−0.01 (−0.01 to 0.00)	15% (−1% to 28%)	‐	‐	‐	13% (−5% to 28%)
Vesikari 2016^b Karppinen 2019^e	‐ ‐	‐ ‐	‐ ‐	‐ ‐	0.99 1.0	1.01 1.3	−0.02^d −0.3 (−0.7 to 0.1)	6% (−6% to 17%) 23% (0% to 40%)
Prymula 2006	‐	‐	‐	‐	0.08	0.13	−0.04^d	34% (21% to 44%)
PCV administered at a later age
*CRM197‐PCV7 followed by PPV23*
Veenhoven 2003	‐	‐	‐	−25% (−57% to 1%)	1.1	0.83	−0.27^d	−29%^h (−62% to −2%)
van Kempen 2006	‐	‐	‐	‐	0.78	0.67	−0.11^d	−16%^h (−96% to 31%)
*CRM197‐PCV7/TIV*
Jansen 2008	‐	‐	‐	‐	‐	‐	‐	57% (6% to 80%)^f
*CRM197‐PCV9*
Dagan 2001	‐	‐	‐	‐	0.66	0.79	−0.14 (−0.29 to 0.02)	17% (−2% to 33%)
CI: confidence interval CRM197‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV7/TIV: trivalent influenza vaccine plus 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV9: 9‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 HBV: hepatitis B virus 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) PPV23: 23‐valent pneumococcal polysaccharide vaccine TIV: trivalent influenza vaccine VE: vaccine efficacy ^aPositive effect estimates indicate a relative reduction in the risk (e.g. 6% means that the vaccine reduces the risk by 6%); negative effect estimates indicate a relative increase in the risk (e.g. −5% means that the vaccine increases the risk by 5%). ^bCluster‐randomised controlled trial. ^cDefined as primary efficacy analysis. Analysis is not entirely according to intention‐to‐treat principle, as 88/944 children were not included in the analysis due to not meeting strict chart review criteria. ^d95% CI could not be calculated, as person‐time across treatment groups was not reported. ^eRespiratory tract infections with acute otitis media was used as the outcome measure. The PHiD‐CV10 and control vaccine groups were statistically different from each other in terms of type of residential area, presence of older siblings, and socioeconomic status of the family. ^fIndex group: CRM197‐PCV7/TIV, control: HBV/placebo; VE placebo/TIV versus HBV/placebo: 71% (95% CI 30% to 88%), that is larger VE placebo/TIV versus HBV/placebo than CRM197‐PCV7/TIV versus HBV/placebo. ^hnegative values for VE expressed as relative reduction in risk represent an increase in the risk for acute otitis media.

Table 1. Effect of pneumococcal conjugate vaccination on frequency of all‐cause acute otitis media episodes

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Table 2. Effect of pneumococcal conjugate vaccination on frequency of pneumococcal acute otitis media episodes

	VE expressed as relative reduction in risk (95% CI)				VE expressed as relative reduction in risk (95% CI)
	Intention‐to‐treat				Per‐protocol
	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
*CRM197‐PCV7*
Black 2000^a Fireman 2003	‐ ‐	65% P = 0.04 ‐	‐ ‐	‐ ‐	‐ ‐	67% P = 0.08 ‐	‐ ‐	‐ ‐
Eskola 2001 Palmu 2009^b	‐ ‐	54% (41% to 64%) ‐	‐ ‐	‐ ‐	34% (21% to 45%) 20% (7% to 31%)	57% (44% to 67%) ‐	51% (27% to 67%) ‐	−33%^d (−80% to 1%) ‐
O'Brien 2008^a,c	‐	64% (−34% to 90%)	‐	‐	‐	‐	‐	‐
*OMPC‐PCV7*
Kilpi 2003	‐	‐	‐	‐	25% (11% to 37%)	56% (44% to 66%)	−5%^d (−47% to 25%)	−27%^d (−70% to 6%)
*PHiD‐PC10 and PHiD‐PC11*
Tregnaghi 2014 Sáez‐Llorens 2017	53% (16% to 74%)	70% (30% to 87%)	29% (−123% to 77%)	15% (−153% to 71%)	56% (13% to 78%)	67% (17% to 87%)	26% (−232% to 83%)	26% (−231% to 83%)
Vesikari 2016^c	‐	‐	‐	‐	‐	‐	‐	‐
Prymula 2006	‐	‐	‐	‐	52% (37% to 63%)	58% (41% to 69%)	66% (22% to 85%)	9% (−64% to 49%)
PCV administered at a later age
*CRM197‐PCV7 followed by PPV23*
Veenhoven 2003	‐	‐	‐	‐	34% P = 0.22	52% P = 0.21	‐	21% P = 0.44
van Kempen 2006	‐	‐	‐	‐	‐	‐	‐	‐
*CRM197‐PCV7/TIV*
Jansen 2008	‐	‐	‐	‐	‐	‐	‐	‐
*CRM197‐PCV9*
Dagan 2001	‐	‐	‐	‐	‐	‐	‐	‐
AOM: acute otitis media CI: confidence interval CRM197‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV7/TIV: trivalent influenza vaccine plus 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV9: 9‐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 PPV23: 23‐valent pneumococcal polysaccharide vaccine TIV: trivalent influenza vaccine VE: vaccine efficacy ^aMiddle ear fluid collected from spontaneous draining ears; in the other studies middle ear fluid was routinely collected during AOM episodes through paracentesis. ^bAdditional analysis of Eskola 2001 including pneumococcal AOM by a positive culture or polymerase chain reaction (PCR). ^cCluster‐randomised controlled trial. ^dnegative values represent an increase in the risk of AOM.

Table 2. Effect of pneumococcal conjugate vaccination on frequency of pneumococcal acute otitis media episodes

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Table 3. Effect of pneumococcal conjugate vaccination on frequency of recurrent acute otitis media

	VE expressed as relative reduction in risk (95% CI)	VE expressed as relative reduction in risk (95% CI)
	Intention‐to‐treat	Per‐protocol
PCV administered in infancy
CRM197‐PCV7
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%)
O'Brien 2008^a	‐	‐
OMPC‐PCV7
Kilpi 2003	‐	‐
PHiD‐PC10 and PHiD‐PC11
Tregnaghi 2014 Sáez‐Llorens 2017	‐	‐
Vesikari 2016^a	‐	‐
Prymula 2006	‐	56% (−2% to 81%)
PCV administered at a later age
CRM197‐PCV7 followed by PPV23
Veenhoven 2003	‐	‐
van Kempen 2006	‐	‐
CRM197‐PCV7/TIV
Jansen 2008	‐	‐
CRM197‐PCV9
Dagan 2001	‐	‐
CI: confidence interval CRM197‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV7/TIV: trivalent influenza vaccine plus 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV9: 9‐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 PPV23: 23‐valent pneumococcal polysaccharide vaccine TIV: trivalent influenza vaccine VE: vaccine efficacy ^aCluster‐randomised controlled trial

Table 3. Effect of pneumococcal conjugate vaccination on frequency of recurrent acute otitis media

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Table 4. Adverse effects

Study ID	No. of participants	PCV type	Redness	Swelling	Pain/tenderness	Fever	Serious adverse events
Black 2000/Fireman 2003	37,868	CRM197‐PCV7	Depending on timing of dose, redness occurred in around 10% to 14% of children receiving CRM197‐PCV7 versus 5% to 9% of children receiving MenC vaccination. More severe redness (> 3 cm) occurred in 0% to 0.6% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and MenC groups.	Depending on timing of dose, swelling occurred in around 10% to 12% of children receiving CRM197‐PCV7 versus 3% to 8% of children receiving MenC vaccination. More severe swelling (> 3 cm) occurred in 0.1% to 0.6% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and MenC groups.	Depending on timing of dose, tenderness was reported in 15% to 23% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and MenC groups.	Depending on timing of dose, fever > 38 °C occurred in around 15% to 24% of children receiving CRM197‐PCV7 versus 9% to 17% of children receiving MenC vaccination. Fever (> 39 °C) occurred in 0.9% to 2.5% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and MenC groups.	No severe adverse events related to vaccination resulting in hospitalisation, emergency, or clinic visits were reported.
Dagan 2001	264	CRM197‐PCV9	Depending on timing of dose, redness occurred in 5% to 6% of children receiving CRM197‐PCV9 versus 0% to 5% of children receiving MenC vaccination.	Depending on timing of dose, swelling occurred in 7% to 12% of children receiving CRM197‐PCV9 versus 0% to 5% of children receiving MenC vaccination.	Depending on timing of dose, tenderness was reported in 25% to 38% of children receiving CRM197‐PCV9 versus 0% to 8% of children receiving MenC vaccination.	Depending on timing of dose, fever > 38 °C occurred in around 15% to 44% of children receiving CRM197‐PCV9 versus 8% to 25% of children receiving MenC vaccination. Fever (> 39.5 °C) occurred in only 1 child receiving CRM197‐PCV9 versus 3 children receiving MenC vaccination.	Not reported
Eskola 2001/Palmu 2009	1662	CRM197‐PCV7	Depending on timing of dose, redness occurred in 14% to 20% of children receiving CRM197‐PCV7 versus 9% to 16% of children receiving hepatitis vaccines. More severe redness (> 2.5 cm) occurred in 0% to 0.9% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and hepatitis vaccine groups.	Depending on timing of dose, swelling occurred in 5% to 6% of children receiving CRM197‐PCV7 versus 2% to 6% of children receiving hepatitis vaccines. More severe swelling (> 2.5 cm) occurred in 0.5% to 1.3% of children receiving CRM197‐PCV7, and did not differ significantly between CRM197‐PCV7 and hepatitis vaccine groups.	Depending on timing of dose, pain was reported in 3% to 8% of children receiving CRM197‐PCV7 versus 2% to 3% of children receiving hepatitis vaccines.	Fever (> 39 °C) occurred in 0.4% to 2.0% of children receiving CRM197‐PCV7 versus 0.2% to 1.7% of children receiving hepatitis vaccines.	No significant differences between vaccine groups were observed for unexpected events (6 versus 4 events). 1 child in the CRM197‐PCV7 group died from bowel obstruction, necrosis, and shock at the age of 8 months (85 days after administration of third dose), but death was assessed as unrelated to study vaccine (autopsy revealed mesenteric defects with volvulus and other congenital abnormalities).
Jansen 2008	579	CRM197‐PCV7/TIV	‐	‐	‐	‐	Quote: “In general, the vaccinations were well‐tolerated, and no immediate or severe adverse events were recorded.”
Kilpi 2003	1666	OMPC‐PCV7	OMPC‐PCV7 caused local reactions within 3 days of each dose more often than the hepB vaccine (data not shown).	OMPC‐PCV7 caused local reactions within 3 days of each dose more often than the hepB vaccine (data not shown).	Not reported	Not reported	There were no statistically significant differences in the occurrence of any diagnosis among individuals who experienced serious adverse events between the 2 vaccine groups. 1 child in the OMPC‐PCV7 group died from volvulus due to bowel obstruction. Death was assessed as unrelated to study vaccine.
Prymula 2006	4968	PHiD‐CV11	Not reported	Not reported	Not reported	Not reported	The percentages of infants with unsolicited symptoms that were judged to be causally related to vaccination were similar in the PHiD‐CV11 and hepA groups (2.5% versus 3.0%). 14 serious adverse events were judged to be causally related to vaccination: 8 occurred in children receiving PHiD‐CV11 vaccination (7 after co‐administration with Infanrix hexa and 1 after PHiD‐CV11 booster) versus 6 in children receiving hepatitis A control vaccine (7 after co‐administration with Infanrix hexa and 1 after hepatitis A booster with Infanrix hexa). All events, apart from 1 case of epilepsy in the hepatitis A group, resolved without sequelae. 4 children died during the study, 1 in the PHiD‐CV11 group (8 months after third dose, diagnosis of epilepsy was made; 25 months after the third dose the child had grand mal epilepsy and died from suffocation). None of the deaths were regarded by the investigators as related to the study vaccine.
Tregnaghi 2014/Sáez‐Llorens 2017	23,821	PHiD‐CV10	Not reported	Not reported	Not reported	Not reported	Serious adverse events did not differ significantly between PHiD‐CV10 and hepatitis control vaccines (21.5% versus 22.6%). Only 1 event (in the control group) was judged to be causally related to vaccination by the investigator, and it resolved without sequelae. 19 children died in the PHiD‐CV10 group (0.16%) versus 26 in the control group (0.22%). None of the deaths were considered by the investigator to be causally related to vaccination.
Veenhoven 2003	383	CRM197‐PCV7	Not reported	Not reported	Not reported	Not reported	No serious adverse events were noted after administration of CRM197‐PCV7 or hepatitis control vaccines.
Vesikari 2016	6178	PHiD‐CV10	Not reported	Not reported	Not reported	Not reported	Serious adverse events considered by the investigator to be causally related to vaccination were reported in 4 infants in the PHiD‐CV10 group (all in 3 + 1 group: sepsis with non‐specified aetiology in 1 infant, pyrexia in 1 infant, convulsion in 2 infants) and in 2 infants in hepB group (petit mal epilepsy in 1 infant and pyrexia in 1 infant). 1 fatal serious adverse event (sudden infant death, not considered to be vaccination related) was reported in the PHiD‐CV10 (2 + 1) group.
CRM197‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV7/TIV: trivalent influenza vaccine plus 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV9: 9‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 hepA: hepatitis A hepB: hepatitis B MenC: meningococcus type C OMPC‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to the outer membrane protein complex of Neisseria meningitidis serogroup B 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) TIV: trivalent influenza vaccine

Table 4. Adverse effects

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Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

PICO

PICO

Population

Intervention

Comparison

Outcome

Plain language summary

Pneumococcal vaccination for preventing acute middle ear infections in children

Resumen visual

Authors' conclusions

Implications for practice

Implications for research

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Outcome reporting bias

Publication bias

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

Included studies

Study designs

Study populations (early infancy versus later in life)

Interventions

Type of PCV used and co‐administration of other vaccines

Comparator

Outcome measures

Funding and conflicts of interest

Brief overview of clinical heterogeneity across included studies

Excluded studies

Ongoing studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Adverse effects (co‐primary outcome)

Acute otitis media outcomes (co‐primary outcome and secondary outcomes)

Effect of PCV administered in early infancy (predominantly < 6 months of age)

PCV7