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Protecting children with HIV against pneumococcal disease
Reflection and Reaction
Protecting children with HIV against pneumococcal disease
Roger Harris/Science Photo Library
Rwanda has become the first developing nation to introduce pneumococcal conjugate vaccine. The aim is to vaccinate nearly all Rwandan infants by the end of 2009. However, equally at risk older children with HIV are unfortunately not yet on the agenda.1 WHO estimates that disease due to Streptococcus pneumoniae claims the lives of up to 1 million children every year.2 These deaths are disproportionately represented in the developing world, particularly in children infected with HIV3 of whom there are about 2 million in sub-Saharan Africa alone. Streptococcus pneumoniae is a Gram-positive bacterium that has been long recognised as a major cause of pneumonia, meningitis, severe sepsis, and other invasive and non-invasive infections.2 91 immunologically distinct capsular serotypes have been identified4 and the distribution of serotype-specific disease varies across populations.5 Those at greatest risk of pneumococcal disease include infants, young children, children exposed to crowding such as in childcare centres, elderly people, and those with predisposing conditions such as HIV/ AIDS3,6,7 and sickle cell disease. Enormous effort has been expended through the Pneumococcal Accelerated Development and Introduction Plan (pneumoADIP) towards routine
Streptococcus pneumoniae claims the lives of up to 1 million children a year, those with HIV are at high risk
394
vaccination with the seven-valent pneumococcal conjugate vaccine (PCV-7) for young infants in resource-poor countries. This effort ignores the needs of millions of older children with HIV/AIDS that are at equal or greater risk of invasive pneumococcal disease.6 These children are frequently under routine medical care and managed with expensive antiretroviral therapy, so the opportunity exists to begin pneumococcal immunoprophylaxis. We argue that the funding for immunoprophylaxis requires serious and immediate consideration. By contrast with children not infected with HIV, whose chances of pneumococcal disease substantially decline with age, children infected with HIV remain at considerable risk even as they grow older.7 Among people infected with HIV, the threat of pneumococcal disease remains high not only at all ages but also at all clinical stages.3 In adults, the incidence of pneumococcal disease is up to 300-times higher among those with HIV infection compared with those without.6 African children infected with HIV that are younger than 2 years have about 40-times greater risk of invasive pneumococcal disease than their HIV-uninfected counterparts.3 The incidence of clinical pneumonia is ten-times higher in children infected with HIV rather than uninfected children.8 Furthermore, case fatality associated with invasive pneumococcal disease is higher among African children infected with HIV than in uninfected children.3 Safe and effective vaccines have been formulated,9,10 including PCV-7, which is now licensed in 90 countries, and has been given to more than 30 million children. PCV-7 covers serotypes 4, 6b, 9V, 14, 18, 19F, and 23F, the most commonly isolated serotypes from paediatric invasive pneumococcal disease in the prevaccine era in many countries. These serotypes have tendencies to antibiotic non-susceptibility, and commonly cause serious, difficult to treat infections with high fatalities.2,11 A review of published work by William Hausdorff and colleagues12 estimates that 70–75% of pneumococcal disease in young African children is caused by serotypes covered by PCV-7.5 Worldwide, PCV-7’s serotype coverage is highest in children younger than 2 years, and then tends to fall rapidly as children grow older. However, individuals with HIV are more commonly infected with these paediatric serotypes irrespective of age.6 www.thelancet.com/infection Vol 9 July 2009
Reflection and Reaction
The focus of vaccination with PCV-7 has so far been directed towards infants, as outlined in the 2007 WHO pneumococcal vaccine position paper.2 There have been very large reductions in disease burden in countries where the vaccine has been introduced into the routine immunisation schedule for infants.9,13 Immunisation of older age groups, especially those more vulnerable to pneumococcal disease, is now an important area of investigation. In particular, unvaccinated children over 4 months of age infected with HIV (ie, beyond the age of routine vaccination as per the WHO Expanded Program on Immunization) might benefit greatly from PCV-7 vaccination.7 A recent pivotal trial in South Africa, found that 83–91% of invasive pneumococcal isolates were covered by the nine-valent pneumococcal conjugate vaccine.10 The vaccine was effective in 65% of the children that were HIV-positive.7 Research on carriage in families with individuals infected with HIV might be revealing. Nasopharyngeal carriage of S pneumoniae is an important step in the acquisition and spread of disease.14 It takes more serum antibody to prevent carriage than disease, so if vaccination prevents carriage it necessarily protects against disease.15 Furthermore, the added impact of highly active antiretroviral therapy (HAART) and immune reconstitution on nasopharyngeal carriage should also be researched. We find it perverse that PCV-7 is now supplied in 26 countries, 24 of which are high-income, have low childhood mortality, and low prevalence of HIV infection. The children in developing countries who desperately need the vaccine are the very ones still denied it.16 The call is increasing to make the worldwide introduction of pneumococcal conjugate vaccines an urgent public health priority.6,16 We propose urgent implementation for children with HIV. Paediatric HAART can now be purchased through special mechanisms for as little as US$200 per year, the expected cost to recipient countries of Global Alliance for Vaccines and Immunization funded PCV-7 might be in the order of $1 per three dose course. Global vaccination of children against pneumococcal disease is important, but will take time; we argue that vaccinating children that are HIV-positive is more feasible and worth implementing now.
www.thelancet.com/infection Vol 9 July 2009
Andrea Meehan, Grant Mackenzie, Delane Shingadia, *Robert Booy Teule Hospital, Diana Centre for HIV and Palliative Care, Muheza, Tanzania (AM); National Centre for Immunisation Research and Surveillance of Vaccine Preventable Disease, The Children’s Hospital at Westmead and The University of Sydney, New South Wales, Australia (AM, RB), Academic Unit of Child Health, Queen Mary’s School of Medicine and Dentistry at Barts and the London, London, UK (RB); Medical Research Council Laboratories, Fajara, The Gambia (GM); and Great Ormond Street Hospital, London, UK (DS) [email protected] AM has done research partly funded by Wyeth. GM declares no conflicts of interest. DS has received research funding from Glaxo Wellcome. RB has received funding to attend and speak at meetings, as well as for research, from CSL, Roche, Sanofi, GlaxoSmithKline, and Wyeth. 1
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Pneumococcal vaccines accelerated development and introduction plan. Rwanda becomes first developing nation to introduce vaccine for world’s leading infectious child killer. http://www.pneumoadip.org/news/ releases/upload/Press-Release_Rwanda_Introduces_PCV.pdf (accessed June 2, 2009). Pneumococcal conjugate vaccine for childhood immunization—WHO position paper. Wkly Epidemiol Rec 2007; 82: 93–104. Madhi SA, Petersen K, Madhi A, Wasas A, Klugman KP. Impact of human immunodeficiency virus type 1 on the disease spectrum of Streptococcus pneumoniae in South African children. Pediatr Infect Dis J 2000; 19: 1141–47. Park IH, Pritchard DG, Cartee R, Brandao A, Brandileone MC, Nahm MH. Discovery of a new capsular serotype (6C) within serogroup 6 of Streptococcus pneumoniae. J Clin Microbiol 2007 45: 1225–33. Hausdorff WP, Feikin DR, Klugman KP. Epidemiological differences among pneumococcal serotypes. Lancet Infect Dis 2005; 5: 83–93. Bliss SJ, O’Brien KL, Janoff EN, et al. The evidence for using conjugate vaccines to protect HIV-infected children against pneumococcal disease. Lancet Infect Dis 2008; 8: 67–80. Berkley JA, Lowe BS, Mwangi I, et al. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med 2005; 352: 39–47. Madhi SA, Kuwanda L, Cutland C, Klugman KP. The impact of a 9-valent pneumococcal conjugate vaccine on the public health burden of pneumonia in HIV-infected and -uninfected children. Clin Infect Dis 2005; 40: 1511–18. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000; 19: 187–95. Klugman KP, Madhi SA, Huebner RE, et al. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003; 349: 1341–48. Klugman KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990; 3: 171–96. Hausdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin Infect Dis 2000; 30: 100–21. Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003; 348: 1737–46. Ghaffar F, Friedland IR, McCracken GH Jr. Dynamics of nasopharyngeal colonization by Streptococcus pneumoniae. Pediatr Infect Dis J 1999; 18: 638–46. Millar EV, O’Brien KL, Bronsdon MA, et al. Anticapsular serum antibody concentration and protection against pneumococcal colonization among children vaccinated with 7-valent pneumococcal conjugate vaccine. Clin Infect Dis 2007; 44: 1173–79. Centers for Disease Control and Prevention. Progress in introduction of pneumococcal conjugate vaccine—worldwide, 2000–2008. MMWR Morb Mortal Wkly Rep 2008; 57: 1148–51.
395
Protecting children with HIV against pneumococcal disease
Roger Harris/Science Photo Library
Rwanda has become the first developing nation to introduce pneumococcal conjugate vaccine. The aim is to vaccinate nearly all Rwandan infants by the end of 2009. However, equally at risk older children with HIV are unfortunately not yet on the agenda.1 WHO estimates that disease due to Streptococcus pneumoniae claims the lives of up to 1 million children every year.2 These deaths are disproportionately represented in the developing world, particularly in children infected with HIV3 of whom there are about 2 million in sub-Saharan Africa alone. Streptococcus pneumoniae is a Gram-positive bacterium that has been long recognised as a major cause of pneumonia, meningitis, severe sepsis, and other invasive and non-invasive infections.2 91 immunologically distinct capsular serotypes have been identified4 and the distribution of serotype-specific disease varies across populations.5 Those at greatest risk of pneumococcal disease include infants, young children, children exposed to crowding such as in childcare centres, elderly people, and those with predisposing conditions such as HIV/ AIDS3,6,7 and sickle cell disease. Enormous effort has been expended through the Pneumococcal Accelerated Development and Introduction Plan (pneumoADIP) towards routine
Streptococcus pneumoniae claims the lives of up to 1 million children a year, those with HIV are at high risk
394
vaccination with the seven-valent pneumococcal conjugate vaccine (PCV-7) for young infants in resource-poor countries. This effort ignores the needs of millions of older children with HIV/AIDS that are at equal or greater risk of invasive pneumococcal disease.6 These children are frequently under routine medical care and managed with expensive antiretroviral therapy, so the opportunity exists to begin pneumococcal immunoprophylaxis. We argue that the funding for immunoprophylaxis requires serious and immediate consideration. By contrast with children not infected with HIV, whose chances of pneumococcal disease substantially decline with age, children infected with HIV remain at considerable risk even as they grow older.7 Among people infected with HIV, the threat of pneumococcal disease remains high not only at all ages but also at all clinical stages.3 In adults, the incidence of pneumococcal disease is up to 300-times higher among those with HIV infection compared with those without.6 African children infected with HIV that are younger than 2 years have about 40-times greater risk of invasive pneumococcal disease than their HIV-uninfected counterparts.3 The incidence of clinical pneumonia is ten-times higher in children infected with HIV rather than uninfected children.8 Furthermore, case fatality associated with invasive pneumococcal disease is higher among African children infected with HIV than in uninfected children.3 Safe and effective vaccines have been formulated,9,10 including PCV-7, which is now licensed in 90 countries, and has been given to more than 30 million children. PCV-7 covers serotypes 4, 6b, 9V, 14, 18, 19F, and 23F, the most commonly isolated serotypes from paediatric invasive pneumococcal disease in the prevaccine era in many countries. These serotypes have tendencies to antibiotic non-susceptibility, and commonly cause serious, difficult to treat infections with high fatalities.2,11 A review of published work by William Hausdorff and colleagues12 estimates that 70–75% of pneumococcal disease in young African children is caused by serotypes covered by PCV-7.5 Worldwide, PCV-7’s serotype coverage is highest in children younger than 2 years, and then tends to fall rapidly as children grow older. However, individuals with HIV are more commonly infected with these paediatric serotypes irrespective of age.6 www.thelancet.com/infection Vol 9 July 2009
Reflection and Reaction
The focus of vaccination with PCV-7 has so far been directed towards infants, as outlined in the 2007 WHO pneumococcal vaccine position paper.2 There have been very large reductions in disease burden in countries where the vaccine has been introduced into the routine immunisation schedule for infants.9,13 Immunisation of older age groups, especially those more vulnerable to pneumococcal disease, is now an important area of investigation. In particular, unvaccinated children over 4 months of age infected with HIV (ie, beyond the age of routine vaccination as per the WHO Expanded Program on Immunization) might benefit greatly from PCV-7 vaccination.7 A recent pivotal trial in South Africa, found that 83–91% of invasive pneumococcal isolates were covered by the nine-valent pneumococcal conjugate vaccine.10 The vaccine was effective in 65% of the children that were HIV-positive.7 Research on carriage in families with individuals infected with HIV might be revealing. Nasopharyngeal carriage of S pneumoniae is an important step in the acquisition and spread of disease.14 It takes more serum antibody to prevent carriage than disease, so if vaccination prevents carriage it necessarily protects against disease.15 Furthermore, the added impact of highly active antiretroviral therapy (HAART) and immune reconstitution on nasopharyngeal carriage should also be researched. We find it perverse that PCV-7 is now supplied in 26 countries, 24 of which are high-income, have low childhood mortality, and low prevalence of HIV infection. The children in developing countries who desperately need the vaccine are the very ones still denied it.16 The call is increasing to make the worldwide introduction of pneumococcal conjugate vaccines an urgent public health priority.6,16 We propose urgent implementation for children with HIV. Paediatric HAART can now be purchased through special mechanisms for as little as US$200 per year, the expected cost to recipient countries of Global Alliance for Vaccines and Immunization funded PCV-7 might be in the order of $1 per three dose course. Global vaccination of children against pneumococcal disease is important, but will take time; we argue that vaccinating children that are HIV-positive is more feasible and worth implementing now.
www.thelancet.com/infection Vol 9 July 2009
Andrea Meehan, Grant Mackenzie, Delane Shingadia, *Robert Booy Teule Hospital, Diana Centre for HIV and Palliative Care, Muheza, Tanzania (AM); National Centre for Immunisation Research and Surveillance of Vaccine Preventable Disease, The Children’s Hospital at Westmead and The University of Sydney, New South Wales, Australia (AM, RB), Academic Unit of Child Health, Queen Mary’s School of Medicine and Dentistry at Barts and the London, London, UK (RB); Medical Research Council Laboratories, Fajara, The Gambia (GM); and Great Ormond Street Hospital, London, UK (DS) [email protected] AM has done research partly funded by Wyeth. GM declares no conflicts of interest. DS has received research funding from Glaxo Wellcome. RB has received funding to attend and speak at meetings, as well as for research, from CSL, Roche, Sanofi, GlaxoSmithKline, and Wyeth. 1
2 3
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5 6
7 8
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11 12
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Pneumococcal vaccines accelerated development and introduction plan. Rwanda becomes first developing nation to introduce vaccine for world’s leading infectious child killer. http://www.pneumoadip.org/news/ releases/upload/Press-Release_Rwanda_Introduces_PCV.pdf (accessed June 2, 2009). Pneumococcal conjugate vaccine for childhood immunization—WHO position paper. Wkly Epidemiol Rec 2007; 82: 93–104. Madhi SA, Petersen K, Madhi A, Wasas A, Klugman KP. Impact of human immunodeficiency virus type 1 on the disease spectrum of Streptococcus pneumoniae in South African children. Pediatr Infect Dis J 2000; 19: 1141–47. Park IH, Pritchard DG, Cartee R, Brandao A, Brandileone MC, Nahm MH. Discovery of a new capsular serotype (6C) within serogroup 6 of Streptococcus pneumoniae. J Clin Microbiol 2007 45: 1225–33. Hausdorff WP, Feikin DR, Klugman KP. Epidemiological differences among pneumococcal serotypes. Lancet Infect Dis 2005; 5: 83–93. Bliss SJ, O’Brien KL, Janoff EN, et al. The evidence for using conjugate vaccines to protect HIV-infected children against pneumococcal disease. Lancet Infect Dis 2008; 8: 67–80. Berkley JA, Lowe BS, Mwangi I, et al. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med 2005; 352: 39–47. Madhi SA, Kuwanda L, Cutland C, Klugman KP. The impact of a 9-valent pneumococcal conjugate vaccine on the public health burden of pneumonia in HIV-infected and -uninfected children. Clin Infect Dis 2005; 40: 1511–18. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000; 19: 187–95. Klugman KP, Madhi SA, Huebner RE, et al. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003; 349: 1341–48. Klugman KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990; 3: 171–96. Hausdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin Infect Dis 2000; 30: 100–21. Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003; 348: 1737–46. Ghaffar F, Friedland IR, McCracken GH Jr. Dynamics of nasopharyngeal colonization by Streptococcus pneumoniae. Pediatr Infect Dis J 1999; 18: 638–46. Millar EV, O’Brien KL, Bronsdon MA, et al. Anticapsular serum antibody concentration and protection against pneumococcal colonization among children vaccinated with 7-valent pneumococcal conjugate vaccine. Clin Infect Dis 2007; 44: 1173–79. Centers for Disease Control and Prevention. Progress in introduction of pneumococcal conjugate vaccine—worldwide, 2000–2008. MMWR Morb Mortal Wkly Rep 2008; 57: 1148–51.
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