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Restraining the pneumococcus
Comment
In The Lancet Infectious Diseases, Pauline Waight and colleagues1 present the results of their comprehensive assessment of changes in invasive pneumococcal disease in England and Wales since the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7), in 2006, and its replacement, PCV13, in 2010. The incidence rates of invasive pneumococcal disease have declined substantially since the introduction of these vaccines and have reached their lowest levels yet; in the epidemiological year 2013/14, incidence in children less than 2 years of age was 77% lower than pre2006 rates. Young children were the target population of the vaccination programme because they are at high risk of invasive pneumococcal disease and its sequelae. Yet, young children comprised only a small proportion of those who ultimately benefited from vaccination. Indirect protection in older, unvaccinated groups accounted for a sizable proportion of the overall effect of PCVs. The largest numbers of prevented cases were in adults of age 45–64 years and 65 years and older. These age groups had relatively high rates of disease before vaccine introduction and experienced declines of 54% and 40%, respectively. These remarkable reductions in invasive pneumococcal disease are in line with descriptions of the effect of these vaccines in the USA.2 The experience with PCV13 reprises both the causes for celebration and caution experienced with PCV7. When PCV7 was introduced, nasopharyngeal carriage of vaccine serotypes and invasive pneumococcal disease caused by these serotypes rapidly decreased in vaccinated populations. Although vaccine serotypes gradually disappeared, the overall proportion of children whose nasopharynx was colonised by the pneumococcus did not change much. Serotypes not included in PCV7 rapidly occupied the biological niche left by disappearing PCV7 serotypes.3–5 Consistent with the pathogenesis of invasive pneumococcal disease, whereby colonisation precedes infection, some nonvaccine serotypes became leading causes of invasive pneumococcal disease in vaccinated populations, partially blunting the gains made in the reduction of all invasive pneumococcal disease. These changes were also noted in older, unvaccinated groups, and although overall invasive pneumococcal disease was markedly reduced after introduction of PCV7,6 these findings www.thelancet.com/infection Vol 15 May 2015
provided part of the rationale for the introduction of PCV13, a new vaccine with expanded serotype coverage. PCV13 was introduced on the basis of immunogenicity rather than efficacy studies. Confirmation of the effectiveness against both the original seven and the additional six serotypes in PCV13 was one major objective of invasive pneumococcal disease surveillance activities. In England and Wales, invasive pneumococcal disease from PCV7 serotypes continued to decrease after PCV13 introduction, and invasive pneumococcal disease from the additional six serotypes decreased rapidly as well. Although reduction of specific PCV13 serotype disease appears consistent in general, changes in invasive pneumococcal disease caused by the less frequent serotypes 3 and 5 were harder to characterise. The other major objective of invasive pneumococcal disease surveillance was to determine whether new nonPCV13 serotypes would emerge as clinically significant causes of invasive pneumococcal disease, an important lesson from the PCV7 experience. The results of the England and Wales data analysis show the emergence of invasive pneumococcal disease due to a diverse array of non-vaccine serotypes during the early postPCV13 years. These residual non-vaccine serotypes were unusual causes of invasive pneumococcal disease in the pre-conjugate vaccine era, and we do not know whether this emergent trend will continue or whether it represents natural fluctuations that are unrelated to vaccine introduction. Despite encouraging news of continuing decrease in overall invasive pneumococcal disease, the studies from England and Wales1 and the USA2 prompt questions about the endgame for the pneumococcus. In an optimistic scenario, only a limited number of the more than 90 known serotypes would cause substantial disease, and the current vaccine or one of higher valency would restrain most invasive pneumococcal disease. Alternatively, other residual virulent serotypes might continue to emerge with each new higher valency vaccine, until an effective universal pneumococcal vaccine or some other solution becomes available. Modelling of changes in pneumococcal carriage and disease after vaccine introduction, coupled with detailed characterisation of specific serotypes, could help inform future choices of vaccine composition.7,8 In addition, careful surveillance studies like those of Waight
Saturn Stills/Science Photo Library
Restraining the pneumococcus
Published Online March 20, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70085-X See Articles page 535
491
Comment
and colleagues1 and Moore and colleagues2 are essential for decisions about next steps. In summarising more than 50 years of research in The Biology of Pneumococcus9 from 1938, Benjamin White wrote in awe of this “altogether amazing cell”, but commented that “man has not been content to allow Pneumococcus to destroy human life in an unrestrained way”. In fact, he noted that “the epidemiologist has attempted to track the mode of dissemination…in the hope of breaking the vicious cycle of transmission from man to man”. White would surely rejoice at the reduction in pneumococcal disease in the 21st century. He would probably not be surprised that the pneumococcus continues to fascinate and provide opportunities for further restraint. *Marie R Griffin, Carlos G Grijalva Department of Health Policy, Vanderbilt University Medical Center, Villlage at Vanderbilt, Nashville, Tennessee 37232, USA marie.griffi[email protected] CGG has served as consultant for GSK and Pfizer and declares grant funding from the US Centers for Disease Control and Prevention and the US Agency for Healthcare Research and Quality, outside of the submitted work. MRG declares grant funding from the US Centers for Disease Control and Prevention, outside of the submitted work.
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Waight PA, Andrews NJ, Ladhani SN, Sheppard CL, Slack MPE, 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; published online March 20. http://dx.doi.org/10.1016/S1473-3099(15)70044-7. 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, populationbased surveillance. Lancet Infect Dis 2015; 15: 301–09. Wroe PC, Lee GM, Finkelstein JA, et al. Pneumococcal carriage and antibiotic resistance in young children before 13-valent conjugate vaccine. Pediatr Infect Dis J 2012; 31: 249–54. 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. van Hoek AJ, Sheppard CL, Andrews NJ, et al. Pneumococcal carriage in children and adults two years after introduction of the thirteen valent pneumococcal conjugate vaccine in England. Vaccine 2014; 32: 4349–55. 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. Flasche S, Edmunds WJ, Miller E, Goldblatt D, Robertson C, Choi YH. The impact of specific and non-specific immunity on the ecology of Streptococcus pneumoniae and the implications for vaccination. Proc Biol Sci 2013; 280: 20131939. Nurhonen M, Auranen K. Optimal serotype compositions for Pneumococcal conjugate vaccination under serotype replacement. PLoS Comput Biol 2014; 10: e1003477. White B, Robinson ES, Barnes LA. The biology of pneumococcus. The bacteriological, biochemical, and immunological characters and activities of Diplococcus pneumoniae. New York: The Commonwealth fund, 1938.
Cristina Pedrazzini/Science Photo Library
Autopsies and better data on causes of death in Africa
Published Online March 10, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70096-4 See Articles page 544
492
Active tuberculosis, particularly when extrapulmonary or disseminated, can be extremely difficult to diagnose before death and is often missed, including as a cause of death. Therefore, autopsy studies can be especially informative. In their classic 1960 study, Petersdorf and Beeson1 identified tuberculosis as the most common cause of fever of unknown origin; most cases were extrapulmonary, and although most were diagnosed both before and after death, one case was only identified after death. In the same decade, autopsy played a crucial part in defining cryptic disseminated tuberculosis as a variant of reactivated tuberculosis that occurred particularly in elderly Scottish women and that was difficult to diagnose.2 More recently, autopsy studies have helped delineate the spectrum of HIV-associated disease in Africa and have shown that active tuberculosis in all its forms is a common cause of adult death.3,4 The global burden of tuberculosis remains immense. In 2014, WHO reported that as many as 3 million people with active tuberculosis remained undiagnosed
and thus untreated, 1·5 million people died from tuberculosis in 2014, and the situation with multidrug resistant tuberculosis is worsening.5 These estimates remain imprecise because of ongoing challenges with diagnosis, inadequate case reporting, and the poor state of vital statistics and death registration in most lowincome and middle-income countries. More accurate estimates of the burden of tuberculosis and the number of deaths from tuberculosis are crucial for appropriate resource allocation to improve case detection, reduce tuberculosis transmission, and achieve global tuberculosis control. The results of the meticulous autopsy study in Zambia by Matthew Bates and colleagues6 published in The Lancet Infectious Diseases are thus timely and important. Bates and colleagues highlight the substantial burden of active tuberculosis in adult patients (≥16 years) who died on adult general medical wards at a tertiary care centre in Lusaka. Overall, over 80% of patients had underlying HIV infection. Active tuberculosis was present in nearly www.thelancet.com/infection Vol 15 May 2015
In The Lancet Infectious Diseases, Pauline Waight and colleagues1 present the results of their comprehensive assessment of changes in invasive pneumococcal disease in England and Wales since the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7), in 2006, and its replacement, PCV13, in 2010. The incidence rates of invasive pneumococcal disease have declined substantially since the introduction of these vaccines and have reached their lowest levels yet; in the epidemiological year 2013/14, incidence in children less than 2 years of age was 77% lower than pre2006 rates. Young children were the target population of the vaccination programme because they are at high risk of invasive pneumococcal disease and its sequelae. Yet, young children comprised only a small proportion of those who ultimately benefited from vaccination. Indirect protection in older, unvaccinated groups accounted for a sizable proportion of the overall effect of PCVs. The largest numbers of prevented cases were in adults of age 45–64 years and 65 years and older. These age groups had relatively high rates of disease before vaccine introduction and experienced declines of 54% and 40%, respectively. These remarkable reductions in invasive pneumococcal disease are in line with descriptions of the effect of these vaccines in the USA.2 The experience with PCV13 reprises both the causes for celebration and caution experienced with PCV7. When PCV7 was introduced, nasopharyngeal carriage of vaccine serotypes and invasive pneumococcal disease caused by these serotypes rapidly decreased in vaccinated populations. Although vaccine serotypes gradually disappeared, the overall proportion of children whose nasopharynx was colonised by the pneumococcus did not change much. Serotypes not included in PCV7 rapidly occupied the biological niche left by disappearing PCV7 serotypes.3–5 Consistent with the pathogenesis of invasive pneumococcal disease, whereby colonisation precedes infection, some nonvaccine serotypes became leading causes of invasive pneumococcal disease in vaccinated populations, partially blunting the gains made in the reduction of all invasive pneumococcal disease. These changes were also noted in older, unvaccinated groups, and although overall invasive pneumococcal disease was markedly reduced after introduction of PCV7,6 these findings www.thelancet.com/infection Vol 15 May 2015
provided part of the rationale for the introduction of PCV13, a new vaccine with expanded serotype coverage. PCV13 was introduced on the basis of immunogenicity rather than efficacy studies. Confirmation of the effectiveness against both the original seven and the additional six serotypes in PCV13 was one major objective of invasive pneumococcal disease surveillance activities. In England and Wales, invasive pneumococcal disease from PCV7 serotypes continued to decrease after PCV13 introduction, and invasive pneumococcal disease from the additional six serotypes decreased rapidly as well. Although reduction of specific PCV13 serotype disease appears consistent in general, changes in invasive pneumococcal disease caused by the less frequent serotypes 3 and 5 were harder to characterise. The other major objective of invasive pneumococcal disease surveillance was to determine whether new nonPCV13 serotypes would emerge as clinically significant causes of invasive pneumococcal disease, an important lesson from the PCV7 experience. The results of the England and Wales data analysis show the emergence of invasive pneumococcal disease due to a diverse array of non-vaccine serotypes during the early postPCV13 years. These residual non-vaccine serotypes were unusual causes of invasive pneumococcal disease in the pre-conjugate vaccine era, and we do not know whether this emergent trend will continue or whether it represents natural fluctuations that are unrelated to vaccine introduction. Despite encouraging news of continuing decrease in overall invasive pneumococcal disease, the studies from England and Wales1 and the USA2 prompt questions about the endgame for the pneumococcus. In an optimistic scenario, only a limited number of the more than 90 known serotypes would cause substantial disease, and the current vaccine or one of higher valency would restrain most invasive pneumococcal disease. Alternatively, other residual virulent serotypes might continue to emerge with each new higher valency vaccine, until an effective universal pneumococcal vaccine or some other solution becomes available. Modelling of changes in pneumococcal carriage and disease after vaccine introduction, coupled with detailed characterisation of specific serotypes, could help inform future choices of vaccine composition.7,8 In addition, careful surveillance studies like those of Waight
Saturn Stills/Science Photo Library
Restraining the pneumococcus
Published Online March 20, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70085-X See Articles page 535
491
Comment
and colleagues1 and Moore and colleagues2 are essential for decisions about next steps. In summarising more than 50 years of research in The Biology of Pneumococcus9 from 1938, Benjamin White wrote in awe of this “altogether amazing cell”, but commented that “man has not been content to allow Pneumococcus to destroy human life in an unrestrained way”. In fact, he noted that “the epidemiologist has attempted to track the mode of dissemination…in the hope of breaking the vicious cycle of transmission from man to man”. White would surely rejoice at the reduction in pneumococcal disease in the 21st century. He would probably not be surprised that the pneumococcus continues to fascinate and provide opportunities for further restraint. *Marie R Griffin, Carlos G Grijalva Department of Health Policy, Vanderbilt University Medical Center, Villlage at Vanderbilt, Nashville, Tennessee 37232, USA marie.griffi[email protected] CGG has served as consultant for GSK and Pfizer and declares grant funding from the US Centers for Disease Control and Prevention and the US Agency for Healthcare Research and Quality, outside of the submitted work. MRG declares grant funding from the US Centers for Disease Control and Prevention, outside of the submitted work.
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Waight PA, Andrews NJ, Ladhani SN, Sheppard CL, Slack MPE, 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; published online March 20. http://dx.doi.org/10.1016/S1473-3099(15)70044-7. 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, populationbased surveillance. Lancet Infect Dis 2015; 15: 301–09. Wroe PC, Lee GM, Finkelstein JA, et al. Pneumococcal carriage and antibiotic resistance in young children before 13-valent conjugate vaccine. Pediatr Infect Dis J 2012; 31: 249–54. 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. van Hoek AJ, Sheppard CL, Andrews NJ, et al. Pneumococcal carriage in children and adults two years after introduction of the thirteen valent pneumococcal conjugate vaccine in England. Vaccine 2014; 32: 4349–55. 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. Flasche S, Edmunds WJ, Miller E, Goldblatt D, Robertson C, Choi YH. The impact of specific and non-specific immunity on the ecology of Streptococcus pneumoniae and the implications for vaccination. Proc Biol Sci 2013; 280: 20131939. Nurhonen M, Auranen K. Optimal serotype compositions for Pneumococcal conjugate vaccination under serotype replacement. PLoS Comput Biol 2014; 10: e1003477. White B, Robinson ES, Barnes LA. The biology of pneumococcus. The bacteriological, biochemical, and immunological characters and activities of Diplococcus pneumoniae. New York: The Commonwealth fund, 1938.
Cristina Pedrazzini/Science Photo Library
Autopsies and better data on causes of death in Africa
Published Online March 10, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70096-4 See Articles page 544
492
Active tuberculosis, particularly when extrapulmonary or disseminated, can be extremely difficult to diagnose before death and is often missed, including as a cause of death. Therefore, autopsy studies can be especially informative. In their classic 1960 study, Petersdorf and Beeson1 identified tuberculosis as the most common cause of fever of unknown origin; most cases were extrapulmonary, and although most were diagnosed both before and after death, one case was only identified after death. In the same decade, autopsy played a crucial part in defining cryptic disseminated tuberculosis as a variant of reactivated tuberculosis that occurred particularly in elderly Scottish women and that was difficult to diagnose.2 More recently, autopsy studies have helped delineate the spectrum of HIV-associated disease in Africa and have shown that active tuberculosis in all its forms is a common cause of adult death.3,4 The global burden of tuberculosis remains immense. In 2014, WHO reported that as many as 3 million people with active tuberculosis remained undiagnosed
and thus untreated, 1·5 million people died from tuberculosis in 2014, and the situation with multidrug resistant tuberculosis is worsening.5 These estimates remain imprecise because of ongoing challenges with diagnosis, inadequate case reporting, and the poor state of vital statistics and death registration in most lowincome and middle-income countries. More accurate estimates of the burden of tuberculosis and the number of deaths from tuberculosis are crucial for appropriate resource allocation to improve case detection, reduce tuberculosis transmission, and achieve global tuberculosis control. The results of the meticulous autopsy study in Zambia by Matthew Bates and colleagues6 published in The Lancet Infectious Diseases are thus timely and important. Bates and colleagues highlight the substantial burden of active tuberculosis in adult patients (≥16 years) who died on adult general medical wards at a tertiary care centre in Lusaka. Overall, over 80% of patients had underlying HIV infection. Active tuberculosis was present in nearly www.thelancet.com/infection Vol 15 May 2015