Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 May 28;5(5):CD001480.
doi: 10.1002/14651858.CD001480.pub5.

Pneumococcal conjugate vaccines for preventing acute otitis media in children

Alexandre C Fortanier  1 , Roderick P Venekamp, Chantal Wb Boonacker, Eelko Hak, Anne Gm Schilder, Elisabeth Am Sanders, Roger Amj Damoiseaux
Affiliations

Pneumococcal conjugate vaccines for preventing acute otitis media in children

Alexandre C Fortanier et al. Cochrane Database Syst Rev. .

Update in

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 methods: 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 eventsNine 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 infancyPCV7The 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-CV10/11The 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 agePCV7We 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-PCV9In 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).

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.

PubMed Disclaimer

Conflict of interest statement

Alexandre C Fortanier: in 2012, Alexandre C Fortanier was appointed as PhD student at the Julius Center for Health Sciences and Primary Care, University Medical Center, University Utrecht, the Netherlands. This review is an integral part of his PhD programme. Until 2017, Alexandre C Fortanier was employed by Janssen Vaccines & Prevention, Leiden, the Netherlands (formerly Crucell Holland B.V.). Alexandre C Fortanier is currently an employee of Seqirus Netherlands B.V., Amsterdam, the Netherlands. Neither company was involved in any aspect of the submitted work, nor did they act as a commercial sponsor of the review or his PhD programme. His employer has no commercial or vested interest in the findings of this review and does not hold any patent relevant to the review.

Roderick P Venekamp is an Editor for Cochrane Acute Respiratory Infections and Cochrane ENT, but had no role in the editorial process of this review.

Chantal WB Boonacker: none known.

Eelko Hak has authored a paper on the design of the CAPITA study (Netherlands Journal of Medicine), but was not involved in the actual conduct of that study, nor does it pose a conflict of interest to the current work.

Anne GM Schilder: the evidENT team at University College London is supported in part by the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. Our research is funded by the NIHR and EU Horizon2020. I am the national chair of the NIHR Clinical Research Network ENT Specialty. I am the Surgical Specialty Lead for ENT for the Royal College of Surgeons of England's Clinical Trials Initiative. I am co‐investigator on the NIHR PGfAR grant 'Defining best Management for Adults with Chronic RhinOsinusitis: the MACRO Programme'. In my role as director of the NIHR UCLH BRC Deafness and Hearing Problems Theme, I act as an adviser on clinical trial design and delivery to a range of biotech companies.

Elisabeth AM Sanders: for research on pneumococcal vaccines, carriage and surveillance studies, Elisabeth AM Sanders received money paid by governmental agencies and pharmaceutical companies GSK and Pfizer, and paid to the institution or collaborating institutions. Furthermore, Elisabeth AM Sanders has participated in Independent Data Monitoring Committees and Advisory Boards for pharmaceutical companies for vaccine studies and/or respiratory tract infections with fees paid to the institution before 2014. In general, fees were always paid to the institution and used for research purposes.

Roger AMJ Damoiseaux: none known.

Elisabeth AM Sanders and Eelko Hak are authors of studies included in this review (Elisabeth AM Sanders: Jansen 2008; van Kempen 2006; Veenhoven 2003; Eelko Hak: Jansen 2008). To avoid any potential conflicts of interest, other review authors reviewed eligibility and performed 'Risk of bias' assessment and data extraction for these studies.

Clarification statement added from the Co‐ordinating Editor, Mark Jones on 9 March, 2020: this review was found by the Cochrane Funding Arbiters, post‐publication, to be non‐compliant with the Cochrane conflict of interest policy, which includes the relevant parts of the Cochrane Commercial Sponsorship Policy. The next update to the review will have a majority of authors and the lead author free of conflicts of interest. The update will be published in nine months.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Black 2000 {published data only}
    1. Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatric Infectious Disease Journal 2000;19(3):187‐95. - PubMed
    1. Fireman B, Black SB, Shinefield HR, Lee J, Lewis E, Ray P. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatric Infectious Disease Journal 2003;22:10‐6. - PubMed
Dagan 2001 {published data only}
    1. Dagan R, Sikuler‐Cohen M, Zamir O, Janco J, Givon‐Lavi N, Fraser D. Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day‐care center attendees. Pediatric Infectious Disease Journal 2001;20(10):951‐8. - PubMed
Eskola 2001 {published data only}
    1. Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. New England Journal of Medicine 2001;344(6):403‐9. - PubMed
    1. Palmu AA, Saukkoriipi A, Jokinen J, Leinonen M, Kilpi TM. Efficacy of pneumococcal conjugate vaccine against PCR‐positive acute otitis media. Vaccine 2009;27:1490‐1. - PubMed
Jansen 2008 {published data only}
    1. Jansen AG, Sanders EA, Hoes AW, Loon AM, Hak E. Effects of influenza plus pneumococcal conjugate vaccination versus influenza vaccination alone in preventing respiratory tract infections in children: a randomized, double‐blind, placebo‐controlled trial. Journal of Pediatrics 2008;153:764‐70. - PMC - PubMed
Kilpi 2003 {published data only}
    1. Kilpi T, Ahman H, Jokinen J, Lankinen KS, Palmu A, Savolainen H, et al. Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7‐valent pneumococcal polysaccharide‐meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Clinical Infectious Diseases 2003;37(9):1155‐64. - PubMed
O'Brien 2008 {published data only}
    1. O'Brien KL, David AB, Chandran A, Moulton LH, Reid R, Weatherholtz R, et al. Randomized, controlled trial efficacy of pneumococcal conjugate vaccine against otitis media among Navajo and White Mountain Apache infants. Pediatric Infectious Disease Journal 2008;27:71‐3. - PubMed
Prymula 2006 {published data only}
    1. Prymula R, Peeters P, Chrobok V, Kriz P, Novakova E, Kaliskova E, et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non‐typeable Haemophilus influenzae: a randomised double‐blind efficacy study. Lancet 2006;367(9512):740‐8. - PubMed
Tregnaghi 2014 {published data only}
    1. Sáez‐Llorens X, Rowley S, Wong D, Rodríguez M, Calvo A, Troitiño M, et al. Efficacy of 10‐valent pneumococcal non‐typeable Haemophilus influenzae protein D conjugate vaccine against acute otitis media and nasopharyngeal carriage in Panamanian children ‐ a randomized controlled trial. Human Vaccines and Immunotherapeutics 2017;13(6):1‐16. - PMC - PubMed
    1. Tregnaghi MW, Sáez‐Llorens X, López P, Abate H, Smith E, Pósleman A, et al. Efficacy of pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD‐CV) in young Latin American children: a double‐blind randomized controlled trial. PLOS Medicine 2014;11(6):e1001657. - PMC - PubMed
van Kempen 2006 {published data only}
    1. Kempen MJ, Vermeiren JS, Vaneechoutte M, Claeys G, Veenhoven RH, Rijkers GT, et al. Pneumococcal conjugate vaccination in children with recurrent acute otitis media: a therapeutic alternative?. International Journal of Pediatric Otorhinolaryngology 2006;70(2):275‐85. - PubMed
Veenhoven 2003 {published data only}
    1. Veenhoven R, Bogaert D, Uiterwaal C, Brouwer C, Kiezebrink H, Bruin J, et al. Effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study. Lancet 2003;361(9376):2189‐95. - PubMed
Vesikari 2016 {published data only}
    1. Vesikari T, Forsten A, Seppä I, Kaijalainen T, Puumalainen T, Soininen A, et al. Effectiveness of the 10‐valent pneumococcal nontypeable Haemophilus influenzae protein D‐conjugated vaccine (PHiD‐CV) against carriage and acute otitis media ‐ a double‐blind randomized clinical trial in Finland. Journal of the Pediatric Infectious Disease Society 2016;5(3):237‐48. - PMC - PubMed

References to studies excluded from this review

Gisselsson‐Solen 2011 {published data only}
    1. Gisselsson‐Solén M, Melhus A, Hermansson A. Pneumococcal vaccination in children at risk of developing recurrent acute otitis media ‐ a randomized study. Acta Paediatrica 2011;100:1354‐8. - PubMed
Jokinen 2012 {published data only}
    1. Jokinen J, Palmu AA, Kilpi T. Acute otitis media replacement and recurrence in the Finnish otitis media vaccine trial. Clinical Infectious Diseases 2012;55:1673‐6. - PubMed
Le 2007 {published data only}
    1. Le TM, Rovers MM, Veenhoven RH, Sanders EA, Schilder AG. Effect of pneumococcal vaccination on otitis media with effusion in children older than 1 year. European Journal of Pediatrics 2007;166:1049‐52. - PubMed
Palmu 2014 {published data only}
    1. Palmu AA, Jokinen J, Nieminen H, Rinta‐Kokko H, Ruokokoski E, Puumalainen T, et al. Effect of pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD‐CV10) on outpatient antimicrobial purchases: a double‐blind, cluster randomised phase 3‐4 trial. Lancet Infectious Diseases 2014;14(3):205‐12. - PubMed
Palmu 2015a {published data only}
    1. Palmu AA, Kaijalainen T, Jokinen J, Kilpi TM. Efficacy of the 7‐valent pneumococcal conjugate vaccine against acute otitis media caused by serotype 6C pneumococcus. Pediatric Infectious Disease Journal 2015;34(7):796‐7. - PubMed
Palmu 2015b {published data only}
    1. Palmu AA, Jokinen J, Nieminen H, Rinta‐Kokko H, Ruokokoski E, Puumalainen T, et al. Effectiveness of the ten‐valent pneumococcal conjugate vaccine against tympanostomy tube placements in a cluster‐randomized trial. Pediatric Infectious Disease Journal 2015;34(11):1230‐5. - PubMed
Palmu 2018 {published data only}
    1. Palmu AA, Jokinen J, Nieminen H, Rinta‐Kokko H, Ruokokoski E, Puumalainen T, et al. Vaccine‐preventable disease incidence of pneumococcal conjugate vaccine in the Finnish invasive pneumococcal disease vaccine trial. Vaccine 2018;36(14):1816‐22. - PubMed
Roy 2011 {unpublished data only}
    1. Roy E, Steinhoff MC, Omer SB, Arifeen SE, Raqib R, Breiman R, et al. Clinical effectiveness of pneumococcal conjugate vaccine in suppurative otitis media: a randomized controlled trial in Bangladeshi infants. Pediatric Academic Societies Annual Meeting. Boston (MA), USA, April 28‐May 1 2011.
Sarasoja 2013 {published data only}
    1. Sarasoja I, Jokinen J, Lahdenkari M, Kilpi T, Palmu AA. Long‐term effect of pneumococcal conjugate vaccines on tympanostomy tube placements. Pediatric Infectious Disease Journal 2013;32(5):517‐20. - PubMed

Additional references

Ahmed 2014
    1. Ahmed S, Shapiro NL, Bhattacharyya N. Incremental health care utilization and costs for acute otitis media in children. Laryngoscope 2014;124(1):301‐5. - PubMed
Allemann 2017
    1. Allemann A, Frey PM, Brugger SD, Hilty M. Pneumococcal carriage and serotype variation before and after introduction of pneumococcal conjugate vaccines in patients with acute otitis media in Switzerland. Vaccine 2017;35(15):1946‐53. - PubMed
Alpert 2011
    1. Alpert HR, Behm I, Connolly GN, Kabir Z. Smoke‐free households with children and decreasing rates of paediatric clinical encounters for otitis media in the United States. Tobacco Control 2011;20(3):207‐11. - PubMed
Andersen 1982
    1. Andersen PK, Gill RD. Cox regression model for counting processes: a large sample study. Annals of Statistics 1982;10(4):1100‐20.
Atkins 2004
    1. Atkins D, Best D, Briss PA, Eccles M, Falck‐Ytter Y, Flottorp S, et al. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004;328(7454):1490. - PMC - PubMed
Barenkamp 2017
    1. Barenkamp SJ, Chonmaitree T, Hakansson AP, Heikkinen T, King S, Nokso‐Koivisto J, et al. Panel 4: Report of the Microbiology Panel. Otolaryngology Head and Neck Surgery 2017;156(Suppl 4):S51‐62. - PMC - PubMed
Ben‐Shimol 2014
    1. Ben‐Shimol S, Givon‐Lavi N, Leibovitz E, Raiz S, Greenberg D, Dagan R. Near‐elimination of otitis media caused by 13‐valent pneumococcal conjugate vaccine (PCV) serotypes in southern Israel shortly after sequential introduction of 7‐valent/13‐valent PCV. Clinical Infectious Diseases 2014;59(12):1724‐32. - PubMed
Biesbroek 2014
    1. Biesbroek G, Wang X, Keijser BJ, Eijkemans RM, Trzciński K, Rots NY, et al. Seven‐valent pneumococcal conjugate vaccine and nasopharyngeal microbiota in healthy children. Emerging Infectious Diseases Journal 2014;20(2):201‐10. - PMC - PubMed
Block 2006
    1. Block SL. Searching for the Holy Grail of acute otitis media. Archives of Disease in Childhood 2006;91(12):959‐61. - PMC - PubMed
Bluestone 1992
    1. Bluestone CD, Stephenson JS, Martin LM. Ten‐year review of otitis media pathogens. Pediatric Infectious Disease Journal 1992;11(8 Suppl):7‐11. - PubMed
Boonacker 2011
    1. Boonacker CW, Broos PH, Sanders EA, Schilder AG, Rovers MM. Cost effectiveness of pneumococcal conjugate vaccination against acute otitis media in children: a review. Pharmacoeconomics 2011;29(3):199‐211. - PubMed
Casey 2013
    1. Casey JR, Kaur R, Friedel VC, Pichichero ME. Acute otitis media otopathogens during 2008 to 2010 in Rochester, New York. Pediatric Infectious Disease Journal 2013;32:805‐9. - PMC - PubMed
Clarke 2017
    1. Clarke C, Bakaletz LO, Ruiz‐Guiñazú J, Borys D, Mrkvan T. Impact of protein D‐containing pneumococcal conjugate vaccines on non‐typeable Haemophilus influenzae acute otitis media and carriage. Expert Review of Vaccines 2017;16(7):1‐14. - PubMed
Coker 2010
    1. Coker TR, Chan LS, Newberry SJ, Limbos MA, Suttorp MJ, Shekelle PG, et al. Diagnosis, microbial epidemiology, and antibiotic treatment of acute otitis media in children: a systematic review. JAMA 2010;304:2161‐9. - PubMed
Dagan 1997
    1. Dagan R, Melamed R, Zamir O, Leroy O. Safety and immunogenicity of tetravalent pneumococcal vaccines containing 6B, 14, 19F and 23F polysaccharides conjugated to either tetanus toxoid or diphtheria toxoid in young infants and their boosterability by native polysaccharide antigens. Pediatric Infectious Disease Journal 1997;16(11):1053‐9. - PubMed
Dagan 2016
    1. Dagan R, Pelton S, Bakaletz L, Cohen R. Prevention of early episodes of otitis media by pneumococcal vaccines might reduce progression to complex disease. Lancet Infectious Diseases 2016;16(4):480‐92. - PubMed
Eskola 1999
    1. Eskola J, Anttila M. Pneumococcal conjugate vaccines. Pediatric Infectious Disease Journal 1999;18(6):543‐51. - PubMed
Ewald 2016
    1. Ewald H, Briel M, Vuichard D, Kreutle V, Zhydkov A, Gloy V. The clinical effectiveness of pneumococcal conjugate vaccines: a systematic review and meta‐analysis of randomized controlled trials. Deutsches Ärzteblatt International 2016;113(9):139‐46. - PMC - PubMed
Eythorsson 2018
    1. Eythorsson E, Hrafnkelsson B, Erlendsdóttir H, Gudmundsson SA, Kristinsson KG, Haraldsson Á. Decreased acute otitis media with treatment failure after introduction of the ten‐valent pneumococcal Haemophilus influenzae protein D conjugate vaccine. Pediatric Infectious Disease Journal 2018;37(4):361‐6. - PubMed
Faden 1997
    1. Faden H, Duffy L, Wasielewski R, Wolf J, Krystofik D, Tung Y. Relationship between nasopharyngeal colonization and the development of otitis media in children. Tonawanda/Williamsville Pediatrics. Journal of Infectious Diseases 1997;175(6):1440‐5. - PubMed
Forsgren 2008
    1. Forsgren A, Riesbeck K, Janson H. Protein D of Haemophilus influenzae: a protective nontypeable H. influenzae antigen and a carrier for pneumococcal conjugate vaccines. Clinical Infectious Diseases 2008;46(5):726‐31. - PubMed
Gisselsson‐Solen 2017
    1. Gisselsson‐Solen M. Trends in otitis media incidence after conjugate pneumococcal vaccination: a national observational study. Pediatric Infectious Disease Journal 2017;36(11):1027‐31. - PubMed
GRADEpro GDT 2015 [Computer program]
    1. McMaster University (developed by Evidence Prime). GRADEpro GDT. Version accessed 16 August 2018. Hamilton (ON): McMaster University (developed by Evidence Prime), 2015.
Heikkinen 1999
    1. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. New England Journal of Medicine 1999;340(4):260‐4. - PubMed
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Jacobs 1998
    1. Jacobs MR, Dagan R, Appelbaum PC, Burch DJ. Prevalence of antimicrobial‐resistant pathogens in middle ear fluid: multinational study of 917 children with acute otitis media. Antimicrobial Agents and Chemotherapy 1998;42(3):589‐95. - PMC - PubMed
Jahn‐Eimermacher 2007
    1. Jahn‐Eimermacher A, du Prel JB, Schmitt HJ. Assessing vaccine efficacy for the prevention of acute otitis media by pneumococcal vaccination in children: a methodological overview of statistical practice in randomized controlled clinical trials. Vaccine 2007;25(33):6237‐44. - PubMed
Kaur 2017
    1. Kaur R, Morris M, Pichichero M. Epidemiology of acute otitis media in the postpneumococcal conjugate vaccine era. Pediatrics 2017;140(3):e20170181. - PMC - PubMed
Kawai 2018
    1. Kawai K, Adil EA, Barrett D, Manganella J, Kenna MA. Ambulatory visits for otitis media before and after the introduction of pneumococcal conjugate vaccination. Journal of Pediatrics 2018;201:122‐7. - PubMed
Kvaerner 1997
    1. Kvaerner KJ, Nafstad P, Hagen JA, Mair IW, Jaakkola JJ. Recurrent acute otitis media: the significance of age at onset. Acta Oto‐Laryngologica 1997;117(4):578‐84. - PubMed
Lau 2015
    1. Lau WC, Murray M, El‐Turki A, Saxena S, Ladhani S, Long P, et al. Impact of pneumococcal conjugate vaccines on childhood otitis media in the United Kingdom. Vaccine 2015;33(39):5072‐9. - PubMed
Laxminarayan 2013
    1. Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF, Sumpradit N, et al. Antibiotic resistance ‐ the need for global solutions. Lancet Infectious Diseases 2013;13(12):1057‐98. - PubMed
Leach 1994
    1. Leach AJ, Boswell JB, Asche V, Nienhuys TG, Mathews JD. Bacterial colonization of the nasopharynx predicts very early onset and persistence of otitis media in Australian aboriginal infants. Pediatric Infectious Disease Journal 1994;13(11):983‐9. - PubMed
Lefebvre 2011
    1. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Lieberthal 2013
    1. Lieberthal AS, Carroll AE, Chonmaitree T, Ganiats TG, Hoberman A, Jackson MA, et al. The diagnosis and management of acute otitis media. Pediatrics 2013;131(3):e964‐99. - PubMed
Luotonen 1981
    1. Luotonen J, Herva E, Karma P, Timonen M, Leinonen M, Makela PH. The bacteriology of acute otitis media in children with special reference to Streptococcus pneumoniae as studied by bacteriological and antigen detection methods. Scandinavian Journal of Infectious Diseases 1981;13(3):177‐83. - PubMed
Magnus 2012
    1. Magnus MC, Vestrheim DF, Nystad W, Håberg SE, Stigum H. Decline in early childhood respiratory tract infections in the Norwegian mother and child cohort study after introduction of pneumococcal conjugate vaccination. Pediatric Infectious Disease Journal 2012;31(9):951‐5. - PMC - PubMed
Marom 2014
    1. Marom T, Tan A, Wilkinson GS, Pierson KS, Freeman JL, Chonmaitree T. Trends in otitis media‐related health care use in the United States, 2001‐2011. JAMA Pediatrics 2014;168(1):68‐75. - PMC - PubMed
McCullagh 1989
    1. McCullagh P, Nelder JA. Generalized Linear Models. London: Chapman and Hall, 1989.
Monasta 2012
    1. Monasta L, Ronfani L, Marchetti F, Montico M, Vecchi Brumatti L, Bavcar A, et al. Burden of disease caused by otitis media: systematic review and global estimates. PLOS ONE 2012;7(4):e36226. - PMC - PubMed
Moulton 2001
    1. Moulton LH, O'Brien KL, Kohberger R, Chang I, Reid R, Weatherholtz R, et al. Design of a group‐randomized Streptococcus pneumoniae vaccine trial. Controlled Clinical Trials 2001;22:438‐52. - PubMed
NCT01545375
    1. NCT01545375. Evaluation of a vaccine for reducing ear and lung infections in children. clinicaltrials.gov/ct2/show/study/NCT01545375 (first received 6 March 2012).
O'Brien 2003
    1. O'Brien KL, Moulton LH, Reid R, Weatherholtz R, Oski J, Brown L, et al. Efficacy and safety of a seven‐valent conjugate pneumococcal vaccine in American Indian children: group randomized trial. Lancet 2003;362(9381):255‐61. - PubMed
O'Brien 2009
    1. O'Brien MA, Prosser LA, Paradise JL, Ray GT, Kulldorff M, Kurs‐Lasky M. New vaccines against otitis media: projected benefits and cost‐effectiveness. Pediatrics 2009;123:1452‐63. - PubMed
Obaro 1996
    1. Obaro SK, Adegbola RA, Banya WA, Greenwood BM. Carriage of pneumococci after pneumococcal vaccination. Lancet 1996;348(9022):271‐2. - PubMed
Palmu 2013
    1. Palmu AA, Jokinen J, Borys D, Nieminen H, Ruokokoski E, Siira L, et al. Effectiveness of the ten‐valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD‐CV10) against invasive pneumococcal disease: a cluster randomised trial. Lancet 2013;381(9862):214‐22. - PubMed
Pavia 2009
    1. Pavia M, Bianco A, Nobile CG, Marinelli P, Angelillo IF. Efficacy of pneumococcal vaccination in children younger than 24 months: a meta‐analysis. Pediatrics 2009;123(6):e1103‐10. - PubMed
Pettigrew 2017
    1. Pettigrew MM, Alderson MR, Bakaletz LO, Barenkamp SJ, Hakansson AP, Mason KM. Panel 6: Vaccines. Otolaryngology Head and Neck Surgery 2017;156(Suppl 4):76‐87. - PMC - PubMed
Pichichero 2013
    1. Pichichero ME, Casey JR, Almudevar A. Nonprotective responses to pediatric vaccines occur in children who are otitis prone. Pediatric Infectious Disease Journal 2013;32(11):1163‐8. - PMC - PubMed
Poehling 2007
    1. Poehling KA, Szilagyi PG, Grijalva CG, Martin SW, LaFleur B, Mitchel E, et al. Reduction of frequent otitis media and pressure‐equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine. Pediatrics 2007;119(4):707‐15. - PubMed
Review Manager 2014 [Computer program]
    1. Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2015.
Rovers 2006
    1. Rovers MM, Glasziou P, Appelman CL, Burke P, McCormick DP, Damoiseaux RA, et al. Antibiotics for acute otitis media: a meta‐analysis with individual patient data. Lancet 2006;368(9545):1429‐35. - PubMed
Schilder 2016
    1. Schilder AG, Chonmaitree T, Cripps AW, Rosenfeld RM, Casselbrant ML, Haggard MP, et al. Otitis media. Nature Reviews Disease Primer 2016;2:16063. - PMC - PubMed
Shinefield 1999
    1. Shinefield HR, Black S, Ray P, Chang I, Lewis N, Fireman B, et al. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatric Infectious Disease Journal 1999;18(9):757‐63. - PubMed
Sigurðsson 2018
    1. Sigurðsson S, Eythorsson E, Hrafnkelsson B, Erlendsdóttir H, Kristinsson KG, Haraldsson Á. Reduction in all‐cause acute otitis media in children less than three years of age in primary care following pneumococcal vaccination with PHiD‐CV10: a whole population study. Clinical Infectious Diseases 2018 March 30 [Epub ahead of print]. [DOI: 10.1093/cid/ciy233] - DOI - PubMed
Somech 2011
    1. Somech I, Dagan R, Givon‐Lavi N, Porat N, Raiz S, Leiberman A, et al. Distribution, dynamics and antibiotic resistance patterns of Streptococcus pneumoniae serotypes causing acute otitis media in children in southern Israel during the 10 year‐period before the introduction of the 7‐valent pneumococcal conjugate vaccine. Vaccine 2011;29:4202‐9. - PubMed
Sox 2008
    1. Sox CM, Finkelstein JA, Yin R, Kleinman K, Lieu TA. Trends in otitis media treatment failure and relapse. Pediatrics 2008;121:674‐9. - PubMed
Spijkerman 2012
    1. Spijkerman J, Prevaes SM, Gils EJ, Veenhoven RH, Bruin JP, Bogaert D, et al. Long‐term effects of pneumococcal conjugate vaccine on nasopharyngeal carriage of S. pneumoniae,S. aureus,H. influenzae and M. catarrhalis. PLOS ONE 2012;7(6):e39730. - PMC - PubMed
Tamir 2015
    1. Tamir SO, Roth Y, Dalal I, Goldfarb A, Grotto I, Marom T. Changing trends of acute otitis media bacteriology in central Israel in the pneumococcal conjugate vaccines era. Pediatric Infectious Disease Journal 2015;34(2):195‐9. - PubMed
Tamir 2017
    1. Tamir SO, Shemesh S, Oron Y, Marom T. Acute otitis media guidelines in selected developed and developing countries: uniformity and diversity. Archives of Disease in Childhood 2017;102(5):450‐7. - PubMed
Taylor 2012
    1. Taylor S, Marchisio P, Vergison A, Harriague J, Hausdorff WP, Haggard M. Impact of pneumococcal conjugate vaccination on otitis media: a systematic review. Clinical Infectious Diseases 2012;54(12):1765‐73. - PMC - PubMed
van den Bergh 2013
    1. Bergh MR, Spijkerman J, Swinnen KM, François NA, Pascal TG, Borys D, et al. Effects of the 10‐valent pneumococcal nontypeable Haemophilus influenzae protein D‐conjugate vaccine on nasopharyngeal bacterial colonization in young children: a randomized controlled trial. Clinical Infectious Diseases 2013;56(3):e30‐9. - PMC - PubMed
van Gils 2011
    1. Gils EJ, Hak E, Veenhoven RH, Rodenburg GD, Bogaert D, Bruin JP, et al. Effect of seven‐valent pneumococcal conjugate vaccine on Staphylococcus aureus colonisation in a randomised controlled trial. PLOS ONE 2011;6(6):e20229. - PMC - PubMed
Veenhoven 2004
    1. Veenhoven RH, Bogaert D, Schilder AG, Rijkers GT, Uiterwaal CS, Kiezebrink HH, et al. Nasopharyngeal pneumococcal carriage after combined pneumococcal conjugate and polysaccharide vaccination in children with a history of recurrent acute otitis media. Clinical Infectious Diseases 2004;39(7):911‐9. - PubMed
Venekamp 2015
    1. Venekamp RP, Sanders SL, Glasziou PP, Mar CB, Rovers MM. Antibiotics for acute otitis media in children. Cochrane Database of Systematic Reviews 2015, Issue 6. [DOI: 10.1002/14651858.CD000219.pub4] - DOI - PMC - PubMed
WHO 2012
    1. World Health Organization. Pneumococcal vaccines WHO position paper – 2012 – Recommendations. Vaccine 2012;30(32):4717‐8. - PubMed
Wiertsema 2011
    1. Wiertsema SP, Kirkham LA, Corscadden KJ, Mowe EN, Bowman JM, Jacoby P, et al. Predominance of nontypeable Haemophilus influenzae in children with otitis media following introduction of a 3+0 pneumococcal conjugate vaccine schedule. Vaccine 2011;29(32):5163‐70. - PubMed
Wiertsema 2012
    1. Wiertsema SP, Corscadden KJ, Mowe EN, Zhang G, Vijayasekaran S, Coates HL, et al. IgG responses to pneumococcal and Haemophilus influenzae protein antigens are not impaired in children with a history of recurrent acute otitis media. PLOS ONE 2012;7(11):e49061. - PMC - PubMed
Zhou 2008
    1. Zhou F, Shefer A, Kong Y, Nuorti JP. Trends in acute otitis media‐related health care utilization by privately insured young children in the United States, 1997‐2004. Pediatrics 2008;121:253‐60. - PubMed

References to other published versions of this review

Fortanier 2014
    1. Fortanier AC, Venekamp RP, Boonacker CW, Hak E, Schilder AG, Sanders EA, et al. Pneumococcal conjugate vaccines for preventing otitis media. Cochrane Database of Systematic Reviews 2014, Issue 4. [DOI: 10.1002/14651858.CD001480.pub4] - DOI - PubMed
Jansen 2009
    1. Jansen AG, Hak E, Veenhoven RH, Damoiseaux RA, Schilder AG, Sanders EA. Pneumococcal conjugate vaccines for preventing otitis media. Cochrane Database of Systematic Reviews 2009, Issue 2. [DOI: 10.1002/14651858.CD001480.pub3] - DOI - PubMed
Straetemans 2002
    1. Straetemans M, Sanders EA, Veenhoven RH, Schilder AG, Damoiseaux RA, Zielhuis GA. Pneumococcal vaccines for preventing otitis media. Cochrane Database of Systematic Reviews 2002, Issue 2. Art, No.: CD001480. [DOI: 10.1002/14651858.CD001480] - DOI - PubMed
Straetemans 2003
    1. Straetemans M, Sanders EAM, Veenhoven RH, Schilder AGM, Damoiseaux RAMJ, Zielhuis GA. Review of randomized controlled trials on pneumococcal vaccination for prevention of otitis media. Pediatric Infectious Disease Journal 2003;22(6):515‐24. - PubMed
Straetemans 2004
    1. Straetemans M, Sanders EAM, Veenhoven RH, Schilder AGM, Damoiseaux RAMJ, Zielhuis GA. Pneumococcal vaccines for preventing otitis media. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD001480.pub2] - DOI - PubMed

Publication types

Substances