- Email: [email protected]
Defining the role of sequential therapy for H pylori infection
Comment
all of the world’s people will have access to health at an affordable cost. The time is ripe to be bold. A systemlevel approach working towards UHC could have a transformative effect in the battle against poverty, hunger, and disease. If we prioritise health as a human right, in addition to a healthier population, social and economic development will flourish. By focusing on UHC in the post-2015 framework, the international community has an opportunity to endorse a countrydriven agenda, as well as build and improve upon the robust legacy of the MDGs.
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Jeanette Vega The Rockefeller Foundation, New York, NY 10018, USA [email protected] JV is Managing Director of Health for the Rockefeller Foundation. I declare that I have no conflicts of interest.
7
United Nations General Assembly. GA/11326. Adopting consensus text, General Assembly encourages member states to plan, pursue transition of national health care systems towards universal coverage. Dec 12, 2012. http://www.un.org/news/press/docs/2012/ga11326.doc.htm (accessed Jan 10, 2012). Waage J, Banerji R, Campbell O, et al. The Millennium Development Goals: a cross-sectoral analysis and principles for goal setting after 2015. Lancet 2010; 376: 991–1023. Schweitzer J, Makinen M, Wilson L, Heymann M, for Results for Development Institute and Overseas Development Institute. Post-2015 health MDGs. Washington: Results for Development Institute, 2012. UN System Task Team on the post-2015 development agenda. Health in the post-2015 UN development agenda. Thematic think piece from UNAIDS, UNICEF, UNFPA, WHO. May, 2012. http://www.un.org/millenniumgoals/pdf/ think%20pieces/8_health.pdf (accessed Jan 10, 2013). WHO. The world health report 2010. Health systems financing: the path to universal coverage. Geneva: World Health Organization, 2010. Chopra M, Sharkey A, Dalmiya N, Anthony D, Binkin N, on behalf of the UNICEF Equity in Child Survival, Health and Nutrition Analysis Team. Strategies to improve health coverage and narrow the equity gap in child survival, health, and nutrition. Lancet 2012; 380: 1331–40. Boerma T. Measurement of trends and equity in coverage of health interventions in the context of universal health coverage. Meeting report, Rockefeller Foundation Center, Bellagio, Sept 17–21, 2012. http://www. worldwewant2015.org/file/279371/download/302866 (accessed Jan 14, 2012).
Defining the role of sequential therapy for H pylori infection Published Online November 16, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61849-2 See Articles page 205
180
Antibiotic treatment to eradicate chronic Helicobacter pylori infection has become the mainstay of treatment for peptic ulcer disease, and reports indicate that H pylori eradication might also prevent gastric cancer.1,2 The relative effectiveness of different eradication regimens varies between geographical regions, however, and the determination of whether one regimen will perform better than another in a particular population has seemed to require comparative clinical trials. In The Lancet, Jyh-Ming Liou and colleagues3 report findings that lend support to the idea that the best eradication regimen can be reliably predicted if the prevalence of antibioticresistant H pylori in the region is known, as has been previously suggested.4 The investigators present the results of a wellexecuted, randomised, open-label clinical trial that included 900 Taiwanese adults and compared three eradication regimens for H pylori: 14 days of triple therapy (lansoprazole, amoxicillin, and clarithromycin), 14 days of sequential therapy (7 days of lansoprazole and amoxicillin followed by 7 days of lansoprazole, clarithromycin, and metronidazole), and 10 days of sequential therapy (5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole).3 Both of the
metronidazole-containing sequential regimens were more effective in eradicating the infection than was the 14-day triple therapy regimen, although only the 14-day sequential regimen was statistically significantly more effective than 14-day triple therapy (90·7% vs 82·3%; p=0·003). Similarly, eradication success with the 14-day sequential group was greater than in the 10-day group (87·0%), but not statistically significantly so. The most innovative aspects of the study relate to the effect of antibiotic resistance on treatment outcome; in logistic regression models, clarithromycin resistance decreased the effectiveness of all three regimens, and metronidazole resistance decreased the effectiveness of both the sequential regimens. A meta-analysis5 of earlier studies that assessed 10-day sequential therapy in southern Europe and parts of Asia had suggested that the advantage of 10-day sequential therapy over triple therapy was attributable to its greater success against clarithromycin-resistant strains of H pylori. However, this finding was derived from just two studies, which included only 45 patients with clarithromycin-resistant infections.6 The meta-analysis results also suggested that metronidazole resistance did not diminish the success of 10-day sequential therapy in the 71 patients with metronidazole-resistant infections. Thus, Liou www.thelancet.com Vol 381 January 19, 2013
and colleagues’ findings indicate that antimicrobial resistance might reduce the effectiveness of sequential therapy to a greater extent than previously thought, and they give a new perspective to the low success reported with 10-day sequential therapy in trials from Latin America, Turkey, Korea, and China.7–10 Liou and colleagues’ Article is also, to our knowledge, one of the first to suggest that extension of the duration of sequential therapy from 10 days to 14 days might improve eradication in patients with either clarithromycinsensitive or clarithromycin-resistant strains of H pylori. A predictive model based on their resistance and duration data indicated that the outcome of 14-day triple therapy would be inferior to that of 10-day sequential therapy, except in populations with a high prevalence of metronidazole resistance (greater than 40%), and that 14-day sequential therapy would be better than either of the two alternatives except in the unusual circumstances in which metronidazole resistance is highly prevalent and clarithromycin resistance is very rare. Liou and colleagues acknowledge several limitations of their study, and several factors should be addressed before the results of their model can be confidently applied to clinical and public health practice. First, published data for the prevalence of antibiotic resistance are scarce, and the data that do exist might be of uncertain validity and generalisability, or outof-date. In low-income and middle-income countries, where H pylori-associated diseases are most common, obtaining useful data for resistance might be both financially and technically unfeasible. Second, although the predictive model results are intriguing, they are based on small numbers of patients with resistant strains of H pylori, so the effectiveness estimates are all imprecise. Further data showing how antibiotic resistance affects treatment outcome will be essential to provide more confidence in the model’s predictions. From a practical standpoint, clinicians should focus on the factors that they can control—recommending only drug regimens that have been shown to be effective in clinical trials, explaining potential sideeffects, and encouraging compliance. Findings from the Maastricht IV consensus report11 suggest that firstline treatment recommendations should be based on an understanding of the local prevalence of H pylori antimicrobial resistance, and the study by Liou and colleagues lends support to this message. When, as is often the case, local antimicrobial resistance data are www.thelancet.com Vol 381 January 19, 2013
Science Photo Library
Comment
Coloured scanning electron micrograph of Helicobacter pylori (red)
not available, clinicians might find it helpful to ask their patients about any previous use of antibiotics.12,13 Patients with repeated exposures to macrolides should probably receive a bismuth-containing quadruple regimen rather than a clarithromycin-based one. Finally, the choice of an optimal eradication regimen will often depend on how it is to be used. Although the most effective regimen will generally be preferred for treating a patient with peptic ulcer disease, factors such as cost, simplicity of administration, and toxicity profile might tip the balance in favour of a somewhat less effective regimen for a public health programme of gastric cancer prevention. *E Robert Greenberg, William D Chey Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA (ERG); and Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA (WDC) [email protected] ERG declares that he has no conflicts of interest. WDC has served as a consultant for AstraZeneca and Takeda Pharmaceuticals. 1
2
3
4
Ma JL, Zhang L, Brown LM, et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst 2012; 104: 488–92. Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 2008; 372: 392–97. Liou J-M, Chen C-C, Chen MJ, et al, for the Taiwan Helicobacter Consortium. Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial. Lancet 2012; published online Nov 16. http://dx.doi.org/10.1016/S01406736(12)61579-7. Graham DY, Shiotani A. Which therapy for Helicobacter pylori infection? Gastroenterology 2012; 143: 10–12.
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Comment
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Gatta L, Vakil N, Leandro G, Di Mario F, Vaira D. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol 2009; 104: 3069–79. Zullo A, Vaira D, Vakil N, et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment Pharmacol Ther 2003; 17: 719–26. Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet 2011; 378: 507–14. Kadayifci A, Uygun A, Kilciler G, et al. Low efficacy of clarithromycin including sequential regimens for Helicobacter pylori infection. Helicobacter 2012; 17: 121–26. Choi HS, Chun HJ, Park SH, et al. Comparison of sequential and 7-, 10-, 14-d triple therapy for Helicobacter pylori infection. World J Gastroenterol 2012; 18: 2377–82.
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Huang YK, Wu MC, Wang SS, et al. Lansoprazole-based sequential and concomitant therapy for the first-line Helicobacter pylori eradication. J Dig Dis 2012; 13: 232–38. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastricht IV/ Florence consensus report. Gut 2012; 61: 646–64. McNulty CA, Lasseter G, Shaw I, et al. Is Helicobacter pylori antibiotic resistance surveillance needed and how can it be delivered? Aliment Pharmacol Ther 2012; 35: 1221–30. Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007; 102: 1808–25.
More evidence for use of pneumococcal conjugate vaccines Published Online November 16, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61957-6
Science Photo Library
See Articles page 214
182
Pneumococcal conjugate vaccines (PCVs) are among the leading interventions for reducing deaths and improving the health of children around the world. These vaccines are now routinely used in about 88 countries, with the number of countries increasing quickly.1 PCVs are used on various schedules, designed to complement existing schedules for other vaccines that are already part of national immunisation programmes. Until now, however, clinical trial evidence to support some of the different ways PCVs can be used was missing. Results from Arto Palmu and colleagues’ Finnish Invasive Pneumococcal disease (FinIP) vaccine trial2 in The Lancet fill some of these gaps. This cluster randomised trial in Finland showed vaccine efficacy of 93% (95% CI 75–99) to 100% (79–100) against invasive pneumococcal disease for
the ten-valent pneumococcal vaccine formulation. This vaccine is constructed of pneumococcal polysaccharides conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid carriers (PHiD-CV10, marketed under the trade name of Synflorix). PHiD-CV10 was first licensed in 2009 on the basis of a comparable immune response to the already licensed seven-valent pneumococcal conjugate vaccine (Prevnar/Prevenar) and on data showing efficacy against otitis media for an earlier, similar 11-valent version.3 While the data used for licensure showed that PHiD-CV10 would be efficacious against disease, the evidence was somewhat indirect. Palmu and colleagues provide confirmatory, conclusive evidence about the vaccine’s benefits against invasive disease. Additional direct data, from a clinical trial that assessed pneumonia endpoints, have been presented in abstract form, but are not yet published.4 The FinIP trial also provides helpful evidence that different vaccine schedules can be protective. PCV7 was first licensed on a schedule of three primary doses with a booster given at about one year of age; this 3+1 schedule was shown to be efficacious in clinical trials in the USA and Finland.5–7 Another commonly used schedule of three primary doses without a booster (3+0) has been shown in two African clinical trials to be efficacious against pneumonia and invasive disease.8,9 On the basis of the strong evidence provided by these clinical trials, WHO recommended use of PCVs using the 3+0 schedule in 2007;10 more recently, WHO also recommended use of a schedule consisting of two primary doses plus a booster at 9–15 months of age (2+1) as an alternative schedule.11 The 2+1 schedule was www.thelancet.com Vol 381 January 19, 2013
all of the world’s people will have access to health at an affordable cost. The time is ripe to be bold. A systemlevel approach working towards UHC could have a transformative effect in the battle against poverty, hunger, and disease. If we prioritise health as a human right, in addition to a healthier population, social and economic development will flourish. By focusing on UHC in the post-2015 framework, the international community has an opportunity to endorse a countrydriven agenda, as well as build and improve upon the robust legacy of the MDGs.
1
2
3
4
5 6
Jeanette Vega The Rockefeller Foundation, New York, NY 10018, USA [email protected] JV is Managing Director of Health for the Rockefeller Foundation. I declare that I have no conflicts of interest.
7
United Nations General Assembly. GA/11326. Adopting consensus text, General Assembly encourages member states to plan, pursue transition of national health care systems towards universal coverage. Dec 12, 2012. http://www.un.org/news/press/docs/2012/ga11326.doc.htm (accessed Jan 10, 2012). Waage J, Banerji R, Campbell O, et al. The Millennium Development Goals: a cross-sectoral analysis and principles for goal setting after 2015. Lancet 2010; 376: 991–1023. Schweitzer J, Makinen M, Wilson L, Heymann M, for Results for Development Institute and Overseas Development Institute. Post-2015 health MDGs. Washington: Results for Development Institute, 2012. UN System Task Team on the post-2015 development agenda. Health in the post-2015 UN development agenda. Thematic think piece from UNAIDS, UNICEF, UNFPA, WHO. May, 2012. http://www.un.org/millenniumgoals/pdf/ think%20pieces/8_health.pdf (accessed Jan 10, 2013). WHO. The world health report 2010. Health systems financing: the path to universal coverage. Geneva: World Health Organization, 2010. Chopra M, Sharkey A, Dalmiya N, Anthony D, Binkin N, on behalf of the UNICEF Equity in Child Survival, Health and Nutrition Analysis Team. Strategies to improve health coverage and narrow the equity gap in child survival, health, and nutrition. Lancet 2012; 380: 1331–40. Boerma T. Measurement of trends and equity in coverage of health interventions in the context of universal health coverage. Meeting report, Rockefeller Foundation Center, Bellagio, Sept 17–21, 2012. http://www. worldwewant2015.org/file/279371/download/302866 (accessed Jan 14, 2012).
Defining the role of sequential therapy for H pylori infection Published Online November 16, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61849-2 See Articles page 205
180
Antibiotic treatment to eradicate chronic Helicobacter pylori infection has become the mainstay of treatment for peptic ulcer disease, and reports indicate that H pylori eradication might also prevent gastric cancer.1,2 The relative effectiveness of different eradication regimens varies between geographical regions, however, and the determination of whether one regimen will perform better than another in a particular population has seemed to require comparative clinical trials. In The Lancet, Jyh-Ming Liou and colleagues3 report findings that lend support to the idea that the best eradication regimen can be reliably predicted if the prevalence of antibioticresistant H pylori in the region is known, as has been previously suggested.4 The investigators present the results of a wellexecuted, randomised, open-label clinical trial that included 900 Taiwanese adults and compared three eradication regimens for H pylori: 14 days of triple therapy (lansoprazole, amoxicillin, and clarithromycin), 14 days of sequential therapy (7 days of lansoprazole and amoxicillin followed by 7 days of lansoprazole, clarithromycin, and metronidazole), and 10 days of sequential therapy (5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole).3 Both of the
metronidazole-containing sequential regimens were more effective in eradicating the infection than was the 14-day triple therapy regimen, although only the 14-day sequential regimen was statistically significantly more effective than 14-day triple therapy (90·7% vs 82·3%; p=0·003). Similarly, eradication success with the 14-day sequential group was greater than in the 10-day group (87·0%), but not statistically significantly so. The most innovative aspects of the study relate to the effect of antibiotic resistance on treatment outcome; in logistic regression models, clarithromycin resistance decreased the effectiveness of all three regimens, and metronidazole resistance decreased the effectiveness of both the sequential regimens. A meta-analysis5 of earlier studies that assessed 10-day sequential therapy in southern Europe and parts of Asia had suggested that the advantage of 10-day sequential therapy over triple therapy was attributable to its greater success against clarithromycin-resistant strains of H pylori. However, this finding was derived from just two studies, which included only 45 patients with clarithromycin-resistant infections.6 The meta-analysis results also suggested that metronidazole resistance did not diminish the success of 10-day sequential therapy in the 71 patients with metronidazole-resistant infections. Thus, Liou www.thelancet.com Vol 381 January 19, 2013
and colleagues’ findings indicate that antimicrobial resistance might reduce the effectiveness of sequential therapy to a greater extent than previously thought, and they give a new perspective to the low success reported with 10-day sequential therapy in trials from Latin America, Turkey, Korea, and China.7–10 Liou and colleagues’ Article is also, to our knowledge, one of the first to suggest that extension of the duration of sequential therapy from 10 days to 14 days might improve eradication in patients with either clarithromycinsensitive or clarithromycin-resistant strains of H pylori. A predictive model based on their resistance and duration data indicated that the outcome of 14-day triple therapy would be inferior to that of 10-day sequential therapy, except in populations with a high prevalence of metronidazole resistance (greater than 40%), and that 14-day sequential therapy would be better than either of the two alternatives except in the unusual circumstances in which metronidazole resistance is highly prevalent and clarithromycin resistance is very rare. Liou and colleagues acknowledge several limitations of their study, and several factors should be addressed before the results of their model can be confidently applied to clinical and public health practice. First, published data for the prevalence of antibiotic resistance are scarce, and the data that do exist might be of uncertain validity and generalisability, or outof-date. In low-income and middle-income countries, where H pylori-associated diseases are most common, obtaining useful data for resistance might be both financially and technically unfeasible. Second, although the predictive model results are intriguing, they are based on small numbers of patients with resistant strains of H pylori, so the effectiveness estimates are all imprecise. Further data showing how antibiotic resistance affects treatment outcome will be essential to provide more confidence in the model’s predictions. From a practical standpoint, clinicians should focus on the factors that they can control—recommending only drug regimens that have been shown to be effective in clinical trials, explaining potential sideeffects, and encouraging compliance. Findings from the Maastricht IV consensus report11 suggest that firstline treatment recommendations should be based on an understanding of the local prevalence of H pylori antimicrobial resistance, and the study by Liou and colleagues lends support to this message. When, as is often the case, local antimicrobial resistance data are www.thelancet.com Vol 381 January 19, 2013
Science Photo Library
Comment
Coloured scanning electron micrograph of Helicobacter pylori (red)
not available, clinicians might find it helpful to ask their patients about any previous use of antibiotics.12,13 Patients with repeated exposures to macrolides should probably receive a bismuth-containing quadruple regimen rather than a clarithromycin-based one. Finally, the choice of an optimal eradication regimen will often depend on how it is to be used. Although the most effective regimen will generally be preferred for treating a patient with peptic ulcer disease, factors such as cost, simplicity of administration, and toxicity profile might tip the balance in favour of a somewhat less effective regimen for a public health programme of gastric cancer prevention. *E Robert Greenberg, William D Chey Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA (ERG); and Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA (WDC) [email protected] ERG declares that he has no conflicts of interest. WDC has served as a consultant for AstraZeneca and Takeda Pharmaceuticals. 1
2
3
4
Ma JL, Zhang L, Brown LM, et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst 2012; 104: 488–92. Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 2008; 372: 392–97. Liou J-M, Chen C-C, Chen MJ, et al, for the Taiwan Helicobacter Consortium. Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial. Lancet 2012; published online Nov 16. http://dx.doi.org/10.1016/S01406736(12)61579-7. Graham DY, Shiotani A. Which therapy for Helicobacter pylori infection? Gastroenterology 2012; 143: 10–12.
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Comment
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9
Gatta L, Vakil N, Leandro G, Di Mario F, Vaira D. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol 2009; 104: 3069–79. Zullo A, Vaira D, Vakil N, et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment Pharmacol Ther 2003; 17: 719–26. Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet 2011; 378: 507–14. Kadayifci A, Uygun A, Kilciler G, et al. Low efficacy of clarithromycin including sequential regimens for Helicobacter pylori infection. Helicobacter 2012; 17: 121–26. Choi HS, Chun HJ, Park SH, et al. Comparison of sequential and 7-, 10-, 14-d triple therapy for Helicobacter pylori infection. World J Gastroenterol 2012; 18: 2377–82.
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11
12
13
Huang YK, Wu MC, Wang SS, et al. Lansoprazole-based sequential and concomitant therapy for the first-line Helicobacter pylori eradication. J Dig Dis 2012; 13: 232–38. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastricht IV/ Florence consensus report. Gut 2012; 61: 646–64. McNulty CA, Lasseter G, Shaw I, et al. Is Helicobacter pylori antibiotic resistance surveillance needed and how can it be delivered? Aliment Pharmacol Ther 2012; 35: 1221–30. Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007; 102: 1808–25.
More evidence for use of pneumococcal conjugate vaccines Published Online November 16, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61957-6
Science Photo Library
See Articles page 214
182
Pneumococcal conjugate vaccines (PCVs) are among the leading interventions for reducing deaths and improving the health of children around the world. These vaccines are now routinely used in about 88 countries, with the number of countries increasing quickly.1 PCVs are used on various schedules, designed to complement existing schedules for other vaccines that are already part of national immunisation programmes. Until now, however, clinical trial evidence to support some of the different ways PCVs can be used was missing. Results from Arto Palmu and colleagues’ Finnish Invasive Pneumococcal disease (FinIP) vaccine trial2 in The Lancet fill some of these gaps. This cluster randomised trial in Finland showed vaccine efficacy of 93% (95% CI 75–99) to 100% (79–100) against invasive pneumococcal disease for
the ten-valent pneumococcal vaccine formulation. This vaccine is constructed of pneumococcal polysaccharides conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid carriers (PHiD-CV10, marketed under the trade name of Synflorix). PHiD-CV10 was first licensed in 2009 on the basis of a comparable immune response to the already licensed seven-valent pneumococcal conjugate vaccine (Prevnar/Prevenar) and on data showing efficacy against otitis media for an earlier, similar 11-valent version.3 While the data used for licensure showed that PHiD-CV10 would be efficacious against disease, the evidence was somewhat indirect. Palmu and colleagues provide confirmatory, conclusive evidence about the vaccine’s benefits against invasive disease. Additional direct data, from a clinical trial that assessed pneumonia endpoints, have been presented in abstract form, but are not yet published.4 The FinIP trial also provides helpful evidence that different vaccine schedules can be protective. PCV7 was first licensed on a schedule of three primary doses with a booster given at about one year of age; this 3+1 schedule was shown to be efficacious in clinical trials in the USA and Finland.5–7 Another commonly used schedule of three primary doses without a booster (3+0) has been shown in two African clinical trials to be efficacious against pneumonia and invasive disease.8,9 On the basis of the strong evidence provided by these clinical trials, WHO recommended use of PCVs using the 3+0 schedule in 2007;10 more recently, WHO also recommended use of a schedule consisting of two primary doses plus a booster at 9–15 months of age (2+1) as an alternative schedule.11 The 2+1 schedule was www.thelancet.com Vol 381 January 19, 2013