Pneumococcal conjugate vaccines for preventing otitis media

For the current issue of the Journal, we asked Dr Nicole Le Saux to comment on and put into context the recent Cochrane Review on pneumococcal conjugate vaccines for preventing otitis media. Acute otitis media (AOM) is a common respiratory infection in early infancy and childhood. The marginal benefits of antibiotics for AOM in low-risk populations, the increasing problem of bacterial resistance to antibiotics, and the large estimated direct and indirect annual costs associated with otitis media have prompted a search for effective vaccines to prevent AOM. A search was performed of CENTRAL (2013, Issue 11), MEDLINE (1995 to November week 3, 2013), EMBASE (1995 to December 2013), CINAHL (2007 to December 2013), LILACS (2007 to December 2013) and Web of Science (2007 to December 2013). Randomized controlled trials (RCTs) investigating the use of pneumococcal conjugate vaccines (PCVs) in preventing AOM in children ≤12 years of age, with a follow-up of at least six months after vaccination. Two review authors independently assessed trial quality and extracted data. In total, 11 publications, including nine RCTs (n=48,426 children, range 74 to 37,868 children per study), investigating 7- to 11-valent PCVs (with different carrier proteins) were included. Five trials (n=47,108) included infants and four trials (n=1318) included children one to seven years of age who were either healthy (one study, n=264) or had a previous history of upper respiratory tract infection including AOM. The methodological quality of the included studies was evaluated to be moderate to high. There was considerable clinical diversity among studies with respect to study population, type of conjugate vaccine and outcome measures; therefore, results were not pooled. In three studies, a 7-valent PCV (PCV-7) with the carrier protein CRM197 (CRM197-PCV-7) administered during early infancy was associated with a relative risk reduction (RRR) ranging from −5% (95% CI −25% to 12%) in high-risk children to 7% (95% CI 4% to 9%) in low-risk children for all-cause AOM. Another PCV-7, administered in infancy, with an outer membrane protein complex of Neisseria meningitidis serogroup B as a carrier protein, did not reduce overall AOM episodes, while a precursor 11-valent PCV (PCV-11) with Haemophilus influenzae protein D as a carrier protein was associated with an RRR of 34% (95% CI 21% to 44%) for all-cause AOM episodes. A 9-valent PCV (PCV-9) (with CRM197 carrier protein) administered in healthy toddlers was associated with an RRR of 17% (parent-reported) (95% CI −2% to 33%) for otitis media episodes. CRM197-PCV-7 followed by a 23-valent pneumococcal polysaccharide vaccination administered after infancy in older children with a history of AOM showed no beneficial effect on first occurrence and later AOM episodes. In one RCT, children 18 to 72 months of age who received trivalent influenza vaccine/placebo and CRM197-PCV/trivalent influenza vaccine had fewer overall AOM episodes (RRR 71% [95% CI 30% to 88%] and (RRR 57% [95% CI 6% to 80%], respectively) during influenza season compared with those who received hepatitis B virus vaccine/placebo. This study suggests that influenza prevention may be important for AOM prevention, and CRM197-PCV-7 given after infancy may have had a negative effect on AOM occurrence in this setting. Based on current evidence regarding the effects of PCVs for preventing AOM, the licensed CRM197-PCV-7 has modest beneficial effects in healthy infants with a low baseline risk for AOM. Administering PCV-7 in high-risk infants after early infancy and in older children with a history of AOM appears to have no benefit in preventing further episodes. Currently, several RCTs are investigating different (newly licensed, multivalent) PCVs administered during early infancy to establish their effects on AOM. Results of these studies may provide a better understanding of the role of newly licensed, multivalent PCVs in preventing AOM. Also, the impact of carrier protein D, used in certain pneumococcal vaccines, needs to be further established. The full text of the Cochrane Review is available in The Cochrane Library: Fortanier AC, Venekamp RP, Boonacker CWB, Hak E, Schilder AGM, Sanders EAM, Damoiseaux RAMJ. Pneumococcal conjugate vaccines for preventing otitis media. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD001480. DOI:10.1002/14651858.CD001480.pub4. The concept that a single vaccine could prevent AOM is laudable and especially attractive from an antimicrobial stewardship perspective; however, it is unlikely to be realized in the near future. The current PCVs were designed to prevent invasive disease due to Streptococcus pneumoniae. Although conjugated vaccines are effective in decreasing, or even eliminating, mucosal colonization of vaccine-specific serotypes, diseases primarily caused by pneumococcal infection of mucosal surfaces (such as AOM) were not the intended target of these highly effective vaccines and their impact on AOM incidence was never expected to be significant. However, it was hoped that by decreasing the incidence of colonization with S pneumoniae, a small proportion of AOM infections could be prevented and, given the frequency of the diagnosis, the vaccine's impact on resource utilization, particularly for AOM, could be significant. The original studies that used PCV-7 and the CRM conjugate reported that the vaccine had a small effect (<10%) on decreasing the incidence of AOM in general. A study from Quebec that analyzed claims pre- and post-PCV-7 determined a 13.2% decrease in claims for AOM in children <5 years of age (1). An analysis involving eight trials of PCV-7 (in addition to two trials with PCV-9 and PCV-11) confirmed this result (2). First, there are numerous (>90) serotypes of S pneumoniae that colonize the oropharynx and the extent to which the seven (or nine or 11 depending on the vaccine) serotypes contributed to the overall incidence of AOM was small. Furthermore, there may have been subsequent serotype replacement with other types that were equally pathogenic in causing AOM. More recently, several studies have demonstrated that the use of the 13-valent PCV (PCV-13) (which is currently used in Canada) has not only decreased the incidence of AOM caused by vaccine-specific serotypes but also demonstrated a further decrease in penicillin-resistant pneumococcal isolates in AOM and in the nasopharynx (3–5). Overall, these data continue to suggest that the most likely pathogen causing AOM continues to be penicillin-susceptible S pneumoniae, and support the use of amoxicillin as first-line therapy in children with AOM who require antibiotics. A recent study involving a cohort of children <6 years of age with severe AOM reported that the middle ear fluid culture positivity rate for S pneumoniae was lower in children who received PCV-13 compared with children who received PCV-7 or no previous vaccine. Additionally, of the children who received PCV-13, approximately one-half had nontypeable H influenza in their middle ear fluid (6). The replacement of S pneumoniae with other bacterial pathogens and other pneumococcal serotypes will evolve with continued use of PCV-13 and suggests that over time, the efficacy of PCV-13 for all-cause AOM may continue to be limited. To date, most children <4 years of age will have received at least one dose of PCV-13, while those between four and 10 years of age will have received PCV-7 and, if >10 years of age, are likely not to have received a PCV at all. Given the small or modest effect of PCV-7 on AOM as presented in the Cochrane Review, the management of AOM is as important today as it was before the PCV era. Therefore, the management of AOM in children should not be dependent on whether the child has received a vaccine because AOM in all settings is still likely to be caused by S pneumoniae and respond to amoxicillin. This review examining the prevention of AOM with the use of the PCV-7 and the expanded spectrum of 9- and 11-valent (conjugated to protein D) vaccines provides an important benchmark in our quest to preventing this common childhood infection. Although the conjugated vaccines (both H influenzae type b and the PCV) are effective in decreasing (or eliminating) colonization of specific pathogens targeted by the vaccine, these data clearly demonstrate that many other bacteria and serotypes of S pneumoniae can still colonize the nasopharynx and eustachian tube, and are capable of causing AOM. The potential value of altering the ecological niche to eliminate the otitis-prone bacteria is unknown. However, given that many episodes of AOM start with viral infections, which then create a fertile environment for stasis and infection with bacteria, it is tantalizing to consider whether the incidence of AOM could be substantially decreased by preventing viral infections such as influenza or respiratory syncytial virus. One trial in this review demonstrated that the influenza vaccine was more protective against AOM than placebo or PCV (7). Parents should be informed that although there may be increased effectiveness of the 13-valent vaccine for preventing AOM, this has not yet been conclusively demonstrated. The primary benefit of PCVs continues to be prevention of invasive, life-threatening infections in children. Their impact on other noninvasive, primarily mucosal infections, such as AOM, continues to evolve.

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