- Email: [email protected]
The future of paediatric pneumococcal conjugate vaccines
Comment
Pneumococcal conjugate vaccines (PCVs) have been extraordinarily effective in directly reducing the risk of invasive pneumococcal disease, meningitis, pneumonia, and otitis media in children, and have also induced herd protection.1–4 The available PCVs are either ten valent (PCV10) or 13 valent (PCV13), are made by two multinational companies, are given to infants and toddlers in three to four doses, and are distributed least in Asia, despite that being the continent where more children are born than any other. All these characteristics are likely to change over the next decade. In The Lancet Respiratory Medicine, Camelia Savulescu and colleagues5 add to the large body of data on PCV effectiveness by describing the effects of PCV10 and PCV13 on the incidence of invasive pneumococcal disease among children younger than 5 years at nine sites in seven European countries. They compared incidence rate ratios (IRRs) and 95% CIs, calculated individually for each of the 4 years after the vaccines were introduced and pooled for study sites, with the corresponding values before and during use of heptavalent PCV (PCV7). By year 4 after the introduction of PCV10 and PCV13, the pooled IRR for invasive pneumococcal disease caused by any serotype was 0·53 (95% CI 0·43–0·65). The magnitude of this reduction in incidence of invasive pneumococcal disease was significant and is similar to that seen in the UK 4 years after PCV13 was introduced;6 however, it is less than the reduction in incidence of more than 80%, compared with that before PCV7, reported in the USA after the introduction of PCV13.1,7 One reason for the lesser reduction in incidence in Europe is that diversity in vaccination coverage between the countries assessed lowered the pooled value. Nevertheless, even where coverage was high, Savulescu and colleagues’ data suggest that the existing PCV10 and PCV13 formulations are insufficient to reduce the incidence of invasive pneumococcal disease from all circulating pneumococcal serotypes in Europe. Indeed, they noted that the median Simpson diversity index value for serotypes across the countries in their study remained high after the introduction of PCV10 and PCV13 (94%, range 80–95%).5 In developing countries, the diversity of serotypes causing invasive pneumococcal disease (and by extension meningitis and pneumonia) is even wider,8 and, therefore, to further address mortality
due to pneumococcal pneumonia worldwide, future PCVs will need to expand the number of serotypes they include while compromising immunogenicity as little as possible. The findings of Savulescu and colleagues support previous data1,2 that PCV10 and PCV13 or PCV13 alone have an effect irrespective of whether a 2 + 1 or 3 + 1 vaccination schedule is used. The estimated vaccination coverage with a mix of schedules among children younger than 5 years varied from 67% to 98%.5 However, although a consistent increase in non-PCV13 serotypes suggests serotype replacement, the extent of invasive pneumococcal disease caused by these serotypes has been less than the extent of reduction in disease caused by the vaccine serotypes. Although carriage of vaccine serotypes was not studied in this European network, coverage in three sites in the study was low (67–77%),5 and, therefore, the uptake of vaccination needed to maintain herd immunity should be considered. Once circulating strains become rare, cost-effectiveness calculations might shift from the ability of PCVs to protect children directly to their ability to maintain near elimination of circulating vaccine type strains through continued herd immunity. Data are needed on various crucial factors: in which group of children the interruption of vaccine serotype transmission is most relevant; the minimum size of poorly immunised communities needed to maintain transmission; and the minimum community immunisation coverage needed to achieve and maintain herd immunity. In the USA, immunisation of 67–75% children in Massachusetts9 and 58% of Native American children induced herd immunity.10 A prospective surveillance study in Madrid, Spain, followed the effects of PCV13 coverage falling from 95% to 67%. Whereas at peak coverage, incidence of invasive pneumococcal disease due to PCV13 serotypes decreased by 93%, after coverage fell, herd protection was maintained.11 It is not possible to know whether PCV13 serotypes would have fallen further had coverage remained high. In the study by Savulescu and colleagues,5 children at all sites received series of two or three doses plus one booster vaccine dose. Use of booster PCV doses in the second year of life is thought to be important for herd
www.thelancet.com/respiratory Published online March 27, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30111-X
Dr P Marazzi/SPL
The future of paediatric pneumococcal conjugate vaccines
Lancet Respir Med 2017 Published Online March 27, 2017 http://dx.doi.org/10.1016/ S2213-2600(17)30111-X See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(17)30110-8
1
Comment
For more on GAVI see http://www.gavi.org
immunity against less frequently carried invasive strains. For example, loss of protection in older age groups has been seen in Australia for serotype 7F12 and Ghana for serotype 113 when no booster doses were given. Immunisation of children aged at least 9 months might, therefore, be needed for herd immunity, particularly against highly invasive strains. The optimum number of doses needed to ensure herd immunity is unknown, but might be only one plus a booster or even just one dose at the optimum time without a following booster. As the findings of Savulescu and colleagues show, use of PCVs can substantially decrease the incidence of invasive pneumococcal disease despite serotype diversity remaining high.5 Thus, expanded use of available PCVs should be a priority. India, China, and Indonesia have only tiny private markets for PCVs despite having the three largest birth cohorts worldwide. India also has the greatest number of children dying from pneumonia per year.14 PCV13 is being introduced in some high-burden Indian states in 2017 with the support of funding from the vaccine alliance Gavi. It is hoped further government funding will be made available for supplies from local or international manufacturers within the next few years. Despite only two manufacturers having licensed PCVs so far, more than a dozen are developing PCV products, of which at least some are likely to enter the market over the next decade. Increased supply is likely to drive down costs and promote high and sustainable coverage. The success of PCV10 and PCV13 is evident. Penetration into country-based immunisation programmes in the largest countries in Asia will further enhance the effects and affordability of PCVs worldwide. *Keith P Klugman, Gail L Rodgers Bill & Melinda Gates Foundation, 500 5th Avenue North, Seattle, WA 98102, USA [email protected]
2
We declare no competing interests. 1
2 3 4
5
6
7 8
9
10 11
12
13
14
Moore MR, Link-Gelles R, Schaffner W, et al. Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive pneumococcal disease in children and adults in the USA: analysis of multisite, population-based surveillance. Lancet Infect Dis 2015; 15: 301–09. Von Gottberg A, de Gouveia L, Tempia S, et al. Effects of vaccination on invasive pneumococcal disease in South Africa. N Engl J Med 2014; 371: 1889–99. Griffin MR, Zhu Y, Moore MR, Whitney CG, Grijalva CG. US hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med 2013; 369: 155–63. 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. Clin Infect Dis 2014; 59: 1724–32. Savulescu C, Krizova P, Lepoutre A, et al. Impact of higher valency pneumococcal conjugate vaccines on invasive pneumococcal disease in children: results of SpIDnet—an observational multicentre study. Lancet Respir Med 2017; published online March 27. http://dx.doi. org/10.1016/ S2213-2600(17)30110-8. Waight PA, Andrews NJ, Ladhani SN, Sheppard CL, Slack MP, Miller E. Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study. Lancet Infect Dis 2015; 15: 535–43. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010; 201: 32–41. Johnson HL, Deloria-Knoll M, Levine OS, et al. Systematic evaluation of serotypes causing invasive pneumococcal disease among children under five: the pneumococcal global serotype project. PLoS Med 2010; 7: e1000348. Loughlin AM, Hsu K, Silverio AL, Marchant CD, Pelton SI. Direct and indirect effects of PCV13 on nasopharyngeal carriage of PCV13 unique pneumococcal serotypes in Massachusetts’ children Pediatr Infect Dis J 2014; 33: 504–10. Grant LR, Hammitt LL, O’Brien SE, et al. Impact of the 13-valent pneumococcal conjugate vaccine on pneumococcal carriage among American Indians. Pediatr Infect Dis J 2016; 35: 907–14. Picazo J, Ruiz-Contreras J, Casado-Flores J, et al. Effect of the different 13-valent pneumococcal conjugate vaccination uptakes on the invasive pneumococcal disease in children: analysis of a hospital-based and population-based surveillance study in Madrid, Spain, 2007–2015. PLoS One 2017; 12: e0172222. Jayasinghe J, Menzies R, Chiu C, et al. Long-term impact of a “3 + 0” schedule for 7- and 13-valent pneumococcal conjugate vaccines on invasive pneumococcal disease in Australia, 2002–2014. Clin Infect Dis 2017; 64: 175–83. Kwambana-Adams BA, Asiedu-Bekoe F, Sarkodie B, et al. An outbreak of pneumococcal meningitis among older children (≥5 years) and adults after the implementation of an infant vaccination programme with the 13-valent pneumococcal conjugate vaccine in Ghana. BMC Infect Dis 2016; 16: 575. Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet 2016; 388: 3027–35.
www.thelancet.com/respiratory Published online March 27, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30111-X
Pneumococcal conjugate vaccines (PCVs) have been extraordinarily effective in directly reducing the risk of invasive pneumococcal disease, meningitis, pneumonia, and otitis media in children, and have also induced herd protection.1–4 The available PCVs are either ten valent (PCV10) or 13 valent (PCV13), are made by two multinational companies, are given to infants and toddlers in three to four doses, and are distributed least in Asia, despite that being the continent where more children are born than any other. All these characteristics are likely to change over the next decade. In The Lancet Respiratory Medicine, Camelia Savulescu and colleagues5 add to the large body of data on PCV effectiveness by describing the effects of PCV10 and PCV13 on the incidence of invasive pneumococcal disease among children younger than 5 years at nine sites in seven European countries. They compared incidence rate ratios (IRRs) and 95% CIs, calculated individually for each of the 4 years after the vaccines were introduced and pooled for study sites, with the corresponding values before and during use of heptavalent PCV (PCV7). By year 4 after the introduction of PCV10 and PCV13, the pooled IRR for invasive pneumococcal disease caused by any serotype was 0·53 (95% CI 0·43–0·65). The magnitude of this reduction in incidence of invasive pneumococcal disease was significant and is similar to that seen in the UK 4 years after PCV13 was introduced;6 however, it is less than the reduction in incidence of more than 80%, compared with that before PCV7, reported in the USA after the introduction of PCV13.1,7 One reason for the lesser reduction in incidence in Europe is that diversity in vaccination coverage between the countries assessed lowered the pooled value. Nevertheless, even where coverage was high, Savulescu and colleagues’ data suggest that the existing PCV10 and PCV13 formulations are insufficient to reduce the incidence of invasive pneumococcal disease from all circulating pneumococcal serotypes in Europe. Indeed, they noted that the median Simpson diversity index value for serotypes across the countries in their study remained high after the introduction of PCV10 and PCV13 (94%, range 80–95%).5 In developing countries, the diversity of serotypes causing invasive pneumococcal disease (and by extension meningitis and pneumonia) is even wider,8 and, therefore, to further address mortality
due to pneumococcal pneumonia worldwide, future PCVs will need to expand the number of serotypes they include while compromising immunogenicity as little as possible. The findings of Savulescu and colleagues support previous data1,2 that PCV10 and PCV13 or PCV13 alone have an effect irrespective of whether a 2 + 1 or 3 + 1 vaccination schedule is used. The estimated vaccination coverage with a mix of schedules among children younger than 5 years varied from 67% to 98%.5 However, although a consistent increase in non-PCV13 serotypes suggests serotype replacement, the extent of invasive pneumococcal disease caused by these serotypes has been less than the extent of reduction in disease caused by the vaccine serotypes. Although carriage of vaccine serotypes was not studied in this European network, coverage in three sites in the study was low (67–77%),5 and, therefore, the uptake of vaccination needed to maintain herd immunity should be considered. Once circulating strains become rare, cost-effectiveness calculations might shift from the ability of PCVs to protect children directly to their ability to maintain near elimination of circulating vaccine type strains through continued herd immunity. Data are needed on various crucial factors: in which group of children the interruption of vaccine serotype transmission is most relevant; the minimum size of poorly immunised communities needed to maintain transmission; and the minimum community immunisation coverage needed to achieve and maintain herd immunity. In the USA, immunisation of 67–75% children in Massachusetts9 and 58% of Native American children induced herd immunity.10 A prospective surveillance study in Madrid, Spain, followed the effects of PCV13 coverage falling from 95% to 67%. Whereas at peak coverage, incidence of invasive pneumococcal disease due to PCV13 serotypes decreased by 93%, after coverage fell, herd protection was maintained.11 It is not possible to know whether PCV13 serotypes would have fallen further had coverage remained high. In the study by Savulescu and colleagues,5 children at all sites received series of two or three doses plus one booster vaccine dose. Use of booster PCV doses in the second year of life is thought to be important for herd
www.thelancet.com/respiratory Published online March 27, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30111-X
Dr P Marazzi/SPL
The future of paediatric pneumococcal conjugate vaccines
Lancet Respir Med 2017 Published Online March 27, 2017 http://dx.doi.org/10.1016/ S2213-2600(17)30111-X See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(17)30110-8
1
Comment
For more on GAVI see http://www.gavi.org
immunity against less frequently carried invasive strains. For example, loss of protection in older age groups has been seen in Australia for serotype 7F12 and Ghana for serotype 113 when no booster doses were given. Immunisation of children aged at least 9 months might, therefore, be needed for herd immunity, particularly against highly invasive strains. The optimum number of doses needed to ensure herd immunity is unknown, but might be only one plus a booster or even just one dose at the optimum time without a following booster. As the findings of Savulescu and colleagues show, use of PCVs can substantially decrease the incidence of invasive pneumococcal disease despite serotype diversity remaining high.5 Thus, expanded use of available PCVs should be a priority. India, China, and Indonesia have only tiny private markets for PCVs despite having the three largest birth cohorts worldwide. India also has the greatest number of children dying from pneumonia per year.14 PCV13 is being introduced in some high-burden Indian states in 2017 with the support of funding from the vaccine alliance Gavi. It is hoped further government funding will be made available for supplies from local or international manufacturers within the next few years. Despite only two manufacturers having licensed PCVs so far, more than a dozen are developing PCV products, of which at least some are likely to enter the market over the next decade. Increased supply is likely to drive down costs and promote high and sustainable coverage. The success of PCV10 and PCV13 is evident. Penetration into country-based immunisation programmes in the largest countries in Asia will further enhance the effects and affordability of PCVs worldwide. *Keith P Klugman, Gail L Rodgers Bill & Melinda Gates Foundation, 500 5th Avenue North, Seattle, WA 98102, USA [email protected]
2
We declare no competing interests. 1
2 3 4
5
6
7 8
9
10 11
12
13
14
Moore MR, Link-Gelles R, Schaffner W, et al. Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive pneumococcal disease in children and adults in the USA: analysis of multisite, population-based surveillance. Lancet Infect Dis 2015; 15: 301–09. Von Gottberg A, de Gouveia L, Tempia S, et al. Effects of vaccination on invasive pneumococcal disease in South Africa. N Engl J Med 2014; 371: 1889–99. Griffin MR, Zhu Y, Moore MR, Whitney CG, Grijalva CG. US hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med 2013; 369: 155–63. 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. Clin Infect Dis 2014; 59: 1724–32. Savulescu C, Krizova P, Lepoutre A, et al. Impact of higher valency pneumococcal conjugate vaccines on invasive pneumococcal disease in children: results of SpIDnet—an observational multicentre study. Lancet Respir Med 2017; published online March 27. http://dx.doi. org/10.1016/ S2213-2600(17)30110-8. Waight PA, Andrews NJ, Ladhani SN, Sheppard CL, Slack MP, Miller E. Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study. Lancet Infect Dis 2015; 15: 535–43. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010; 201: 32–41. Johnson HL, Deloria-Knoll M, Levine OS, et al. Systematic evaluation of serotypes causing invasive pneumococcal disease among children under five: the pneumococcal global serotype project. PLoS Med 2010; 7: e1000348. Loughlin AM, Hsu K, Silverio AL, Marchant CD, Pelton SI. Direct and indirect effects of PCV13 on nasopharyngeal carriage of PCV13 unique pneumococcal serotypes in Massachusetts’ children Pediatr Infect Dis J 2014; 33: 504–10. Grant LR, Hammitt LL, O’Brien SE, et al. Impact of the 13-valent pneumococcal conjugate vaccine on pneumococcal carriage among American Indians. Pediatr Infect Dis J 2016; 35: 907–14. Picazo J, Ruiz-Contreras J, Casado-Flores J, et al. Effect of the different 13-valent pneumococcal conjugate vaccination uptakes on the invasive pneumococcal disease in children: analysis of a hospital-based and population-based surveillance study in Madrid, Spain, 2007–2015. PLoS One 2017; 12: e0172222. Jayasinghe J, Menzies R, Chiu C, et al. Long-term impact of a “3 + 0” schedule for 7- and 13-valent pneumococcal conjugate vaccines on invasive pneumococcal disease in Australia, 2002–2014. Clin Infect Dis 2017; 64: 175–83. Kwambana-Adams BA, Asiedu-Bekoe F, Sarkodie B, et al. An outbreak of pneumococcal meningitis among older children (≥5 years) and adults after the implementation of an infant vaccination programme with the 13-valent pneumococcal conjugate vaccine in Ghana. BMC Infect Dis 2016; 16: 575. Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet 2016; 388: 3027–35.
www.thelancet.com/respiratory Published online March 27, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30111-X