Pneumococcal vaccination for preventing acute middle ear infections in children

Review question

We reviewed the evidence about 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 Streptococcus 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 29 March 2019. 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, and four trials included 1318 children aged one year and over who were either healthy or who had previous respiratory illness or frequent acute middle ear infections.

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 either increased by 5% in high-risk infants or 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 (to 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 causally related to vaccination were rare and did not differ significantly between vaccine groups.

Quality of the evidence

We assessed the quality of the evidence for PCV7 in early infancy to be high (further research is very unlikely to change our confidence in the estimate of effect). We judged the quality of the evidence for PHiD-CV10 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 quality of the evidence for PCV7 in older children with or without a history of respiratory illness to be high.

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. We found no evidence of a beneficial effect on all-cause AOM of administering PCVs in high-risk infants, after early infancy (i.e. in children one year and above), 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. We found no evidence of a difference in more severe local reactions, fever, or serious adverse events judged causally related to vaccination.

Read the full abstract...
Background: 

Prior to introducing pneumococcal conjugate vaccines (PCVs), Streptococcus pneumoniae was most commonly isolated from 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, and 2014. The review title was changed (to include the population, i.e. children) for this update.

Objectives: 

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

Search strategy: 

We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Web of Science, and trials registers (ClinicalTrials.gov and WHO ICTRP) to 29 March 2019.

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 quality of the evidence.

Main results: 

We included 14 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 two additional trials for this 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, while 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 did not perform meta-analyses.

Adverse events

Nine trials reported on adverse effects (77,389 children; high-quality 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 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.

PCV administered in early infancy

PCV7

The effect of a licenced 7-valent PCV with CRM197 as carrier protein (CRM197-PCV7) on all-cause AOM varied from −5% (95% confidence interval (CI) −25% to 12%) relative risk reduction (RRR) in high-risk infants (1 trial; 944 children; moderate-quality evidence) to 6% (95% CI −4% to 16%; 1 trial; 1662 children) and 6% (95% CI 4% to 9%; 1 trial; 37,868 children) RRR in low-risk infants (high-quality evidence). 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; high-quality 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-quality evidence) and CRM197-PCV7 with 9% (95% CI −12% to 27%) to 10% (95% CI 7% to 13%) RRR in recurrent AOM (2 trials; 39,530 children; high-quality 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 varied from 6% (95% CI −6% to 17%; 1 trial; 5095 children) to 15% (95% CI −1% to 28%; 1 trial; 7359 children) RRR in healthy infants (moderate-quality evidence). PHiD-CV11 was associated with 34% (95% CI 21% to 44%) RRR in all-cause AOM (1 trial; 4968 children; high-quality 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-quality evidence) and PHiD-CV11 with 56% (95% CI −2% to 80%) RRR in recurrent AOM (1 trial; 4968 children; moderate-quality evidence).

PCV administered at 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; high-quality 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; high-quality evidence).

CRM197-PCV9

In 1 trial including 264 healthy day-care attendees aged 1 to 3 years, CRM197-PCV9 was associated with 17% (95% CI −2% to 33%) RRR in parent-reported all-cause OM (low-quality evidence).

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