Evidence for clinicians
Pneumococcal conjugate vaccines for preventing otitis media Nicole Le Saux MD FRCPC
F
or 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. Background 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. Methods Search methods: 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). Selection criteria: 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. Data analysis: Two review authors independently assessed trial quality and extracted data. Results 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. Conclusions 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.
EXPERT COMMENTARY How does this review impact the 2016 Canadian Paediatric Society recommendations for management of AOM? 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
Centre hospitalier pour enfants de l’est de l’Ontario, Ottawa, Ontario Correspondence: Dr Nicole Le Saux, Centre hospitalier pour enfants de l’est de l’Ontario, 401 ch Smyth, Ottawa, Ontario K1H 8L1. Telephone 613-737-7600 ext 2651, e-mail [email protected] Accepted for publication January 26, 2016 Paediatr Child Health Vol 21 No 2 March 2016
©2016 Canadian Paediatric Society. All rights reserved
89
Evidence for Clinicians
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 (
Pneumococcal conjugate vaccines for preventing otitis media Nicole Le Saux MD FRCPC
F
or 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. Background 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. Methods Search methods: 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). Selection criteria: 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. Data analysis: Two review authors independently assessed trial quality and extracted data. Results 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. Conclusions 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.
EXPERT COMMENTARY How does this review impact the 2016 Canadian Paediatric Society recommendations for management of AOM? 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
Centre hospitalier pour enfants de l’est de l’Ontario, Ottawa, Ontario Correspondence: Dr Nicole Le Saux, Centre hospitalier pour enfants de l’est de l’Ontario, 401 ch Smyth, Ottawa, Ontario K1H 8L1. Telephone 613-737-7600 ext 2651, e-mail [email protected] Accepted for publication January 26, 2016 Paediatr Child Health Vol 21 No 2 March 2016
©2016 Canadian Paediatric Society. All rights reserved
89
Evidence for Clinicians
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 (
