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).
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.
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.
To assess the effect of PCVs in preventing AOM in children up to 12 years of age.
We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Web of Science, and two trials registers, ClinicalTrials.gov and WHO ICTRP, to 11 June 2020.
Randomised controlled trials of PCV versus placebo or control vaccine.
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.
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.