The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
Palmu et al
EFFICACY OF THE 7-VALENT PNEUMOCOCCAL CONJUGATE VACCINE AGAINST ACUTE OTITIS MEDIA CAUSED BY SEROTYPE 6C PNEUMOCOCCUS Arto A. Palmu, MD, PhD, Tarja Kaijalainen, PhD, Jukka Jokinen, PhD, and Terhi M. Kilpi, MD, PhD Abstract: A new pneumococcal serotype 6C, earlier typed as 6A, was discovered in 2007. We retyped all 6A isolates to evaluate vaccine efficacy against 6C acute otitis media (AOM) in the phase III randomized, doubleblind Finnish Otitis Media trial conducted in 1995–1999. Efficacy against 6C AOM was −1 (95% confidence interval: −248 to 71) during the per protocol follow-up period. The updated vaccine efficacy estimate for serotype 6A AOM was 65% (95% confidence interval: 31–82). Seven-valent pneumococcal conjugate vaccine offered excellent cross-protection against 6A AOM, but our data do not support cross-protection against 6C AOM. Key Words: conjugate vaccine, pneumococcus, clinical trial, infant, serotype 6C Accepted for publication January 9, 2015. From the Department of Health Protection, National Institute for Health and Welfare, Finland. The FinOM Vaccine Trial was supported by Wyeth-Lederle Vaccines and Pediatrics and Merck & Co. Inc. The National Institute for Health and Welfare has received research funding from GlaxoSmithKline group of companies for a PCV10 trial in which the authors have worked as investigators. Address for correspondence: Arto A. Palmu, MD, PhD, Department of Health Protection, National Institute for Health and Welfare, THL, Finn-Medi I, Biokatu 6, 33520 Tampere, Finland. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000000728
A
novel pneumococcal serotype 6C was discovered in 2007.1 It was earlier identified as serotype 6A in addition to the true 6A serotypes. The first 7-valent pneumococcal conjugate vaccine (PCV7, Prevenar/Prevnar, Pfizer, Philadelphia, PA), including the serotype 6B polysaccharide antigen but not 6A, showed cross-protective immune reaction to 6A.2 This activity was later shown to be clinically protective also against 6A invasive pneumococcal disease.3 In the Finnish Otitis Media (FinOM) vaccine trial conducted in 1995–1999,4 we reported cross-protective serotype-specific vaccine efficacy (VE) of the PCV7 for 6A acute otitis media (AOM) as 57% [95% confidence interval (CI): 24–76]. We retyped all 6A isolates to evaluate the VE against 6C AOM.
study.7 The carriage prevalences at different time-points were compared between the vaccine groups using χ2 test.
RESULTS Eight hundred and thirty-one children were enrolled both in the PCV7 and control arms. In the control group intentionto-treat follow-up, serotype 6C was found in 12.5% (6 of 48) of the episodes originally serotyped as 6A, in 1.3% (6 of 467) of all culture-confirmed pneumococcal AOM and in 0.4% (6 of 1532) of all episodes of AOM confirmed with myringotomy. During the per protocol follow-up period, there were 5 AOM episodes because of serotype 6C both in PCV7 and control groups with an incidence of 0.42 per 100 person-years (VE: −1; 95% CI: −248 to 71). The updated incidence for serotype 6A AOM, now excluding 6C episodes, was 3.4 per 100 person-years in the control group (40 episodes in the control group and 14 in the PCV7 group); the cross-protective PCV7 VE estimate was 65% (95% CI: 31–82). The VE analyses were also performed using intentionto-treat follow-up producing similar results. For carriage, serotype 6C was detected in control vaccine recipients in 20% of the carriage isolates originally serotyped as 6A at 12 and 18 months of age. There was no 6C carriage in the control group at 4–5 years of age. The 6A and 6C carriage prevalences are shown in Figure 1. There were no statistically significant differences in any of the comparisons between carriage prevalences.
DISCUSSION PCV7 offered no cross-protection against 6C AOM but had excellent efficacy against 6A AOM, even higher than reported previously,4 and the updated VE against 6A AOM exceeded the VE point estimate against the vaccine serotypes (57%), yet was lower than VE against 6B AOM (VE: 84%; 95% CI: 62–93). No statistically significant impact on 6A carriage at 12 and 18 months was observed. Thus, in concordance with our previous results,8 it seems that the PCV7 impact against 6A AOM is not mediated through carriage only. To date, FinOM vaccine trial remains the only trial that has evaluated PCV7 efficacy against serotype-specific AOM. The second trial with serotype-specific AOM conducted to estimate the efficacy of the PHiD-CV11, precursor of the PHiD-CV10, showed 63% VE (95% CI: −14 to 88) against 6A AOM, including potential 6C cases.9
METHODS The FinOM vaccine trial was a phase III randomized, double-blind controlled trial conducted in 1995–1999 in Finland.4 Children received PCV7 or hepatitis B vaccine as control at 2, 4, 6 and 12 months of age. Follow-up for AOM was conducted in specific study clinics from 2 to 24 months of age. Myringotomy with middle ear fluid aspiration was performed in each case of AOM. Middle ear fluid samples were cultured, Streptococcus pneumoniae were identified and serotyped using serological methods.5 Per protocol follow-up started 14 days after the third vaccination and ended at 24 months of age or at the time of protocol violation. Intention-to-treat follow-up started at the first vaccine dose and ended at 24 months of age. Generalized Cox regression6 was used to estimate VE against 6A/6C AOM episodes.4 Nasopharyngeal swab samples were taken at 12 and 18 months and also at the age of 4–5 years in long-term follow-up
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FIGURE 1. Nasopharyngeal carriage prevalence (%) of serotypes 6A and 6C at different ages in control and PCV7-vaccinated children in the FinOM trial. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
All PCVs that have been introduced (PCV7, PCV10, PCV13) include the 6B antigen, and the PCV13 includes also the 6A antigen. However, both PCV7 and PCV10 have shown evidence of clinical cross-protection against 6A.10,11 PCV7 has also been shown to induce indirect protection, mediated through carriage, against 6A invasive pneumococcal disease, yet in a longer time frame compared with the true vaccine types.10 Therefore, although we did not observe any statistically significant impact against 6A carriage, the PCV7 appears to have some impact on 6A carriage. There are recent data that PCV13, which includes the 6A antigen, offers cross-protection against 6C carriage12,13 and thus probably also against 6C AOM. The randomized double-blind design with detection of AOM confirmed by myringotomy in high incidence underlines the validity of the serotype-specific results. The reserotyping was performed in a blinded fashion, although study was unblinded already in 1999. However, because of the low occurrence of 6C AOM, our study lacked power, and the confidence intervals for the VE estimate against 6C AOM were wide. This retrospective reanalysis of the pivotal trial data confirms the high cross-protection of PCV7 against serotype 6A but does not support cross-protection against serotype 6C AOM. These data help to interpret the PCV7 data earlier published regarding the serotype 6A.
ACKNOWLEDGMENTS The authors acknowledge Mika Lahdenkari for statistical analysis support. REFERENCES 1. Park IH, Pritchard DG, Cartee R, et al. Discovery of a new capsular serotype (6C) within serogroup 6 of Streptococcus pneumoniae. J Clin Microbiol. 2007;45:1225–1233. 2. Väkeväinen M, Eklund C, Eskola J, et al. Cross-reactivity of antibodies to type 6B and 6A polysaccharides of Streptococcus pneumoniae,
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
PCV7 Efficacy Against 6C
evoked by pneumococcal conjugate vaccines, in infants. J Infect Dis. 2001;184:789–793. 3. Whitney CG, Pilishvili T, Farley MM, et al. Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study. Lancet. 2006;368:1495–1502. 4. Eskola J, Kilpi T, Palmu A, et al; Finnish Otitis Media Study Group. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403–409. 5. Kilpi T, Herva E, Kaijalainen T, et al. Bacteriology of acute otitis media in a cohort of Finnish children followed for the first two years of life. Pediatr Infect. Dis J. 2001;20:654–662. 6. Andersen PK, Gill RD. Cox’s regression model for counting processes: a large sample study. Ann Stat. 1982;10:1100–1120. 7. Palmu AA, Verho J, Jokinen J, et al. The seven-valent pneumococcal conjugate vaccine reduces tympanostomy tube placement in children. Pediatr Infect Dis J. 2004;23:732–738. 8. Kilpi TM, Syrjänen R, Palmu A, et al. Parallel evaluation of the effect of a 7-valent pneumococcal conjugate vaccine (PNCCRM) on pneumococcal (PNC) carriage and acute otitis media (AOM). In: 19th Annual Meeting of the European Society for Pediatric Infectious Diseases (ESPID 2001), Istanbul, Turkey, March 26–28,2001. 9. Prymula R, Peeters P, Chrobok V, et al. Pneumococcal capsular polysaccharides conjugated to protein D provide protection against otitis media caused by both Streptococcus pneumoniae and nontypable Haemophilus influenzae: a randomized double blind efficacy study. Lancet 2006;367:740–748. 10. Park IH, Moore MR, Treanor JJ, et al; Active Bacterial Core Surveillance Team. Differential effects of pneumococcal vaccines against serotypes 6A and 6C. J Infect Dis. 2008;198:1818–1822. 11. Jokinen J, Rinta-Kokko H, Siira L, et al. Impact of ten-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in Finnish children—a population-based study. PLoS One. 2015;10:e0120290. 12. Cooper D, Yu X, Sidhu M, et al. The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A. Vaccine 2011;29:7207–7211. 13. Dagan R, Patterson S, Juergens C, et al. Comparative immunogenicity and efficacy of 13-valent and 7-valent pneumococcal conjugate vaccines in reducing nasopharyngeal colonization: a randomized double-blind trial. Clin Infect Dis. 2013;57:952–962.
www.pidj.com | 797
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Palmu et al
EFFICACY OF THE 7-VALENT PNEUMOCOCCAL CONJUGATE VACCINE AGAINST ACUTE OTITIS MEDIA CAUSED BY SEROTYPE 6C PNEUMOCOCCUS Arto A. Palmu, MD, PhD, Tarja Kaijalainen, PhD, Jukka Jokinen, PhD, and Terhi M. Kilpi, MD, PhD Abstract: A new pneumococcal serotype 6C, earlier typed as 6A, was discovered in 2007. We retyped all 6A isolates to evaluate vaccine efficacy against 6C acute otitis media (AOM) in the phase III randomized, doubleblind Finnish Otitis Media trial conducted in 1995–1999. Efficacy against 6C AOM was −1 (95% confidence interval: −248 to 71) during the per protocol follow-up period. The updated vaccine efficacy estimate for serotype 6A AOM was 65% (95% confidence interval: 31–82). Seven-valent pneumococcal conjugate vaccine offered excellent cross-protection against 6A AOM, but our data do not support cross-protection against 6C AOM. Key Words: conjugate vaccine, pneumococcus, clinical trial, infant, serotype 6C Accepted for publication January 9, 2015. From the Department of Health Protection, National Institute for Health and Welfare, Finland. The FinOM Vaccine Trial was supported by Wyeth-Lederle Vaccines and Pediatrics and Merck & Co. Inc. The National Institute for Health and Welfare has received research funding from GlaxoSmithKline group of companies for a PCV10 trial in which the authors have worked as investigators. Address for correspondence: Arto A. Palmu, MD, PhD, Department of Health Protection, National Institute for Health and Welfare, THL, Finn-Medi I, Biokatu 6, 33520 Tampere, Finland. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000000728
A
novel pneumococcal serotype 6C was discovered in 2007.1 It was earlier identified as serotype 6A in addition to the true 6A serotypes. The first 7-valent pneumococcal conjugate vaccine (PCV7, Prevenar/Prevnar, Pfizer, Philadelphia, PA), including the serotype 6B polysaccharide antigen but not 6A, showed cross-protective immune reaction to 6A.2 This activity was later shown to be clinically protective also against 6A invasive pneumococcal disease.3 In the Finnish Otitis Media (FinOM) vaccine trial conducted in 1995–1999,4 we reported cross-protective serotype-specific vaccine efficacy (VE) of the PCV7 for 6A acute otitis media (AOM) as 57% [95% confidence interval (CI): 24–76]. We retyped all 6A isolates to evaluate the VE against 6C AOM.
study.7 The carriage prevalences at different time-points were compared between the vaccine groups using χ2 test.
RESULTS Eight hundred and thirty-one children were enrolled both in the PCV7 and control arms. In the control group intentionto-treat follow-up, serotype 6C was found in 12.5% (6 of 48) of the episodes originally serotyped as 6A, in 1.3% (6 of 467) of all culture-confirmed pneumococcal AOM and in 0.4% (6 of 1532) of all episodes of AOM confirmed with myringotomy. During the per protocol follow-up period, there were 5 AOM episodes because of serotype 6C both in PCV7 and control groups with an incidence of 0.42 per 100 person-years (VE: −1; 95% CI: −248 to 71). The updated incidence for serotype 6A AOM, now excluding 6C episodes, was 3.4 per 100 person-years in the control group (40 episodes in the control group and 14 in the PCV7 group); the cross-protective PCV7 VE estimate was 65% (95% CI: 31–82). The VE analyses were also performed using intentionto-treat follow-up producing similar results. For carriage, serotype 6C was detected in control vaccine recipients in 20% of the carriage isolates originally serotyped as 6A at 12 and 18 months of age. There was no 6C carriage in the control group at 4–5 years of age. The 6A and 6C carriage prevalences are shown in Figure 1. There were no statistically significant differences in any of the comparisons between carriage prevalences.
DISCUSSION PCV7 offered no cross-protection against 6C AOM but had excellent efficacy against 6A AOM, even higher than reported previously,4 and the updated VE against 6A AOM exceeded the VE point estimate against the vaccine serotypes (57%), yet was lower than VE against 6B AOM (VE: 84%; 95% CI: 62–93). No statistically significant impact on 6A carriage at 12 and 18 months was observed. Thus, in concordance with our previous results,8 it seems that the PCV7 impact against 6A AOM is not mediated through carriage only. To date, FinOM vaccine trial remains the only trial that has evaluated PCV7 efficacy against serotype-specific AOM. The second trial with serotype-specific AOM conducted to estimate the efficacy of the PHiD-CV11, precursor of the PHiD-CV10, showed 63% VE (95% CI: −14 to 88) against 6A AOM, including potential 6C cases.9
METHODS The FinOM vaccine trial was a phase III randomized, double-blind controlled trial conducted in 1995–1999 in Finland.4 Children received PCV7 or hepatitis B vaccine as control at 2, 4, 6 and 12 months of age. Follow-up for AOM was conducted in specific study clinics from 2 to 24 months of age. Myringotomy with middle ear fluid aspiration was performed in each case of AOM. Middle ear fluid samples were cultured, Streptococcus pneumoniae were identified and serotyped using serological methods.5 Per protocol follow-up started 14 days after the third vaccination and ended at 24 months of age or at the time of protocol violation. Intention-to-treat follow-up started at the first vaccine dose and ended at 24 months of age. Generalized Cox regression6 was used to estimate VE against 6A/6C AOM episodes.4 Nasopharyngeal swab samples were taken at 12 and 18 months and also at the age of 4–5 years in long-term follow-up
796 | www.pidj.com
FIGURE 1. Nasopharyngeal carriage prevalence (%) of serotypes 6A and 6C at different ages in control and PCV7-vaccinated children in the FinOM trial. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
All PCVs that have been introduced (PCV7, PCV10, PCV13) include the 6B antigen, and the PCV13 includes also the 6A antigen. However, both PCV7 and PCV10 have shown evidence of clinical cross-protection against 6A.10,11 PCV7 has also been shown to induce indirect protection, mediated through carriage, against 6A invasive pneumococcal disease, yet in a longer time frame compared with the true vaccine types.10 Therefore, although we did not observe any statistically significant impact against 6A carriage, the PCV7 appears to have some impact on 6A carriage. There are recent data that PCV13, which includes the 6A antigen, offers cross-protection against 6C carriage12,13 and thus probably also against 6C AOM. The randomized double-blind design with detection of AOM confirmed by myringotomy in high incidence underlines the validity of the serotype-specific results. The reserotyping was performed in a blinded fashion, although study was unblinded already in 1999. However, because of the low occurrence of 6C AOM, our study lacked power, and the confidence intervals for the VE estimate against 6C AOM were wide. This retrospective reanalysis of the pivotal trial data confirms the high cross-protection of PCV7 against serotype 6A but does not support cross-protection against serotype 6C AOM. These data help to interpret the PCV7 data earlier published regarding the serotype 6A.
ACKNOWLEDGMENTS The authors acknowledge Mika Lahdenkari for statistical analysis support. REFERENCES 1. Park IH, Pritchard DG, Cartee R, et al. Discovery of a new capsular serotype (6C) within serogroup 6 of Streptococcus pneumoniae. J Clin Microbiol. 2007;45:1225–1233. 2. Väkeväinen M, Eklund C, Eskola J, et al. Cross-reactivity of antibodies to type 6B and 6A polysaccharides of Streptococcus pneumoniae,
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
PCV7 Efficacy Against 6C
evoked by pneumococcal conjugate vaccines, in infants. J Infect Dis. 2001;184:789–793. 3. Whitney CG, Pilishvili T, Farley MM, et al. Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study. Lancet. 2006;368:1495–1502. 4. Eskola J, Kilpi T, Palmu A, et al; Finnish Otitis Media Study Group. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403–409. 5. Kilpi T, Herva E, Kaijalainen T, et al. Bacteriology of acute otitis media in a cohort of Finnish children followed for the first two years of life. Pediatr Infect. Dis J. 2001;20:654–662. 6. Andersen PK, Gill RD. Cox’s regression model for counting processes: a large sample study. Ann Stat. 1982;10:1100–1120. 7. Palmu AA, Verho J, Jokinen J, et al. The seven-valent pneumococcal conjugate vaccine reduces tympanostomy tube placement in children. Pediatr Infect Dis J. 2004;23:732–738. 8. Kilpi TM, Syrjänen R, Palmu A, et al. Parallel evaluation of the effect of a 7-valent pneumococcal conjugate vaccine (PNCCRM) on pneumococcal (PNC) carriage and acute otitis media (AOM). In: 19th Annual Meeting of the European Society for Pediatric Infectious Diseases (ESPID 2001), Istanbul, Turkey, March 26–28,2001. 9. Prymula R, Peeters P, Chrobok V, et al. Pneumococcal capsular polysaccharides conjugated to protein D provide protection against otitis media caused by both Streptococcus pneumoniae and nontypable Haemophilus influenzae: a randomized double blind efficacy study. Lancet 2006;367:740–748. 10. Park IH, Moore MR, Treanor JJ, et al; Active Bacterial Core Surveillance Team. Differential effects of pneumococcal vaccines against serotypes 6A and 6C. J Infect Dis. 2008;198:1818–1822. 11. Jokinen J, Rinta-Kokko H, Siira L, et al. Impact of ten-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in Finnish children—a population-based study. PLoS One. 2015;10:e0120290. 12. Cooper D, Yu X, Sidhu M, et al. The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A. Vaccine 2011;29:7207–7211. 13. Dagan R, Patterson S, Juergens C, et al. Comparative immunogenicity and efficacy of 13-valent and 7-valent pneumococcal conjugate vaccines in reducing nasopharyngeal colonization: a randomized double-blind trial. Clin Infect Dis. 2013;57:952–962.
www.pidj.com | 797
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
