- Email: [email protected]
BCG vaccination: a long-lasting protection against tuberculosis? – Authors' reply
Correspondence
1
2
3
4
5
6
7
8
Horby PW, Endzt H, Muyembe-Tamfum JJ, et al. Ebola: Europe–Africa research collaborations. Lancet Infect Dis 2015; 15: 1258–59. Yazdanpanah Y, Horby P, van Griensven J, et al. Drug assessment in the Ebola virus disease epidemic in west Africa. Lancet Infect Dis 2015; 15: 1258. Lanini S, Zumla A, Ioannidis JP, et al. Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa? Lancet Infect Dis 2015; 15: 738–45. Ippolito G, Lanini S, Brouqui P, et al. Ebola: missed opportunities for Europe–Africa research. Lancet Infect Dis 2015; 15: 1254–55. Byar DP, Schoenfeld DA, Green SB, et al. Design considerations for AIDS trials. N Engl J Med 1990; 323: 1343–48. Cohen J, Enserink M. Infectious disease. As Ebola epidemic draws to a close, a thin scientific harvest. Science 2016; 351: 12–13. de Jong MD, Reusken C, Horby P, et al. Preparedness for admission of patients with suspected Ebola virus disease in European hospitals: a survey, August–September 2014. Euro Surveill 2014; 19: 20980. Ippolito G, Feldmann H, Lanini S, et al. Viral hemorrhagic fevers: advancing the level of treatment. BMC Med 2012; 10: 31.
BCG vaccination: a long-lasting protection against tuberculosis? The recent study by Patrick Nguipdop-Djomo and colleagues 1 showed that BCG vaccination conferred long-lasting protection against tuberculosis disease in a large tuberculin skin test (TST) negative population in Norway between 1962 and 1975. Tuberculosis rates were 3·3 per 100 000 person-years in BCG unvaccinated individuals and 1·3 per 100 000 person-years in BCG vaccinated individuals. This study echoes previous studies that BCGderived immunity persists longer than 10–15 years.2 The authors state “Prophylactic treat ment for latent tuberculosis infection was seldom used in Norway before 2002 and therefore was not a concern”, but would isoniazid prevention therapy prescribed from 2002 to 2011 explain the difference in tuberculosis rates if it was more 408
frequently prescribed to BCG vaccinated individuals? Preventive therapy with isoniazid with or without rifamycin can reduce the risk of future disease by 60–90%. 3 Furthermore, the analysis did not describe factors such as exposure to smear-positive cases in the BCG unvaccinated group, immigrants from countries with high tuberculosis burden, HIV positivity, malnutrition, diabetes, silicosis, injection drug abuse, homelessness, chronic renal failure/haemodialysis, gastrectomy, jejunoileal bypass, renal or cardiac transplantation, and carcinoma of the head or neck.4,5 One of the limitations of relying on administrative data might be incomplete risk factor information available for all 381 326 participants compared with that available from tuberculosis registries. It is important to determine whether there is a difference in risk factors rates by BCG vaccination status in the 260 people who developed tuberculosis. If any or some of the risk factors were more likely to be present in the BCG unvaccinated, the vaccine efficacy might have been overestimated. I declare no competing interests.
Eduardo Hernández-Garduño [email protected] Teaching and Research Department, Instituto de Seguridad Social del Estado de México y Municipios (ISSEMyM), Colonia del Parque, Toluca, Estado de México 50180, Mexico 1
2
3
4
5
Nguipdop-Djomo P, Heldal E, Rodrigues LC, et al. Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study. Lancet Infect Dis 2015; 16: 219–26. Aronson NE, Santosham M, Comstock GW, et al. Long-term efficacy of BCG vaccine in American Indians and Alaska natives: a 60-year follow-up study. JAMA 2004; 291: 2086–91. Leung CC, Rieder HL, Lange C, et al. Treatment of latent infection with Mycobacterium tuberculosis: update 2010. Eur Respir J 2011; 37: 690–711. Fox GJ, Barry SE, Britton WJ, Marks GB. Contact investigation for tuberculosis: a systematic review and meta-analysis. Eur Respir J 2013; 41: 140–56. Anon. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000; 49: 1–51.
Authors’ reply We thank Eduardo HernándezGarduño for his interest in our study.1 In his Correspondence, he wonders if differences in treatment for latent tuberculosis infection or other risk factors for tuberculosis in BCG vaccinated groups compared with unvaccinated groups—ie, confounding—could overestimate vaccine effectiveness against tuberculosis. Treatment for latent tuberculosis infection increased very little in the Norwegian-born population from 2002 to 2011, and there is no evidence or reason why prescriptions would differ by vaccination status. We also note that 2002–11 represent at most the past 9 years of the more than 40 years’ follow-up, and is thus unlikely to affect estimates of vaccine effectiveness early on. Furthermore, if BCG vaccination confers some protection against Mycobacterium tuberculosis infection as suggested by emerging evidence,2 then latent tuberculosis infection (and treatment) would be more frequent in the unvaccinated group, with the effect of underestimating rather than overestimating vaccine effectiveness against tuberculosis. It would have been interesting to compare some of the tuberculosis risk factors suggested in the letter between vaccination groups; unfortunately these data were unavailable. However, the distribution of socioeconomic indicators available, including educational attainment, occupation, as well as local tuberculosis rates did not vary much between BCG vaccine recipients and tuberculin-negative non-vaccinated individuals.1 These factors were also found to be only weak confounders in our analysis. HIV was not present in Norway at the start of this study, and the prevalence remains extremely low in the Norwegian-born population. Malnutrition does not seem to be relevant in this setting, and silicosis is rare. More generally, as acknowledged in our study, it is difficult to completely exclude the possibility of residual www.thelancet.com/infection Vol 16 April 2016
Correspondence
confounding in observational studies, be it from unmeasured or unknown confounders. However, in view of the widespread nature of the tuberculosis screening and BCG vaccination programme, it is likely that factors affecting delivery were more important than was individual predisposition to tuberculosis. It is thus unlikely that the distribution of other risk factors would vary very much between unvaccinated and vaccinated individuals after such screening and over the long followup period. Overall, as discussed in our study, it is more likely that our estimates of vaccine effectiveness of 49% (95% CI 26–65) over 40 years are conservative, in view of the characteristics of the study participants and the difficulty of excluding those with previous infection and sensitisation to environmental mycobacteria. LCR, PM, and IA are co-investigators in a separate study of a similar question in another setting (England) funded by a grant from the UK National Institute for Health Research during the conduct of this study. IA reports grants from the UK National Institute for Health Research and British Medical Research Council for other tuberculosis-related research during the conduct of this study. PN-D and EH declare no competing interests.
*Patrick Nguipdop-Djomo, Einar Heldal, Laura Cunha Rodrigues, Ibrahim Abubakar, Punam Mangtani [email protected] Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK 1
2
Nguipdop-Djomo P, Heldal E, Rodrigues LC, Abubakar I, Mangtani P. Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study. Lancet Infect Dis 2016; 16: 219–26. Roy A, Eisenhut M, Harris RJ, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ 2014; 349: g4643.
Is introduction of IPV “Good news for billions of children”? Mass worldwide vaccination with oral polio vaccine (OPV) has resulted in a steep decrease in polio infections and associated paralysis. Since the world www.thelancet.com/infection Vol 16 April 2016
is now close to eradicating polio, vaccine-derived polio constitutes an increasing proportion of overall polio infections. From this perspective, introduction of the more expensive inactivated polio vaccine (IPV) solves a problem as emphasised in the Comment by Kimberley Thompson.1 Passive reporting of adverse events in sequential cohorts could show whether any suspected side-effects suddenly increase with a change in vaccine use. However, it does not provide an overall assessment of whether the vaccine actually benefits the health of children. Studies from Guinea-Bissau have shown important beneficial effects of the OPV on child health: mortality was 32% (95% CI 0–55; HR 0·68 [95% CI 0·45–1·00]) lower among neonates randomly assigned to both OPV and BCG than among those randomly assigned to BCG only.2 Observational studies also support the beneficial non-specific effects of OPV on child mortality, reducing mortality by far more than can be explained by preventing polio infections alone. A recent review commissioned by WHO of the non-specific effects of the live measles and BCG vaccines and the inactivated diphtheria-tetanuspertussis (DTP) vaccine concluded that measles and BCG vaccines could reduce child mortality by up to 50%.3 For the DTP vaccine, most studies indicated a negative effect on child mortality.3 In developing countries, DTP and OPV are administered together; during the early 2000s shortages of DTP vaccine in Guinea-Bissau enabled a study of OPV only versus DTP and OPV coadministration. The hospital case-fatality rate was 0·29 (95% CI 0·11–0·77) for oral polio vaccine only compared with the reference (DTP plus OPV),4 suggesting that the OPV neutralises some of the detrimental effects of the DTP vaccine. In 2008, following the demonstration of methodological flaws in studies concluding that there was no sign of a negative effect of DTP, the Global Advisory Committee on Vaccine
Safety stated that it would monitor the evidence of non-specific effects of vaccines.5 It remains to be assessed whether IPV has non-specific effects and especially whether IPV could be detrimental for child health. IPV has been used as a comparator vaccine in randomised trials; girls randomly assigned to IPV had 52% (95% 2–128) higher mortality than did boys who were randomly assigned to the vaccine.6 Considering the beneficial effects of OPV, the effect on all-cause child mortality of replacing the OPV with the IPV in routine vaccination programmes should be assessed to ensure that it is in fact not bad news for billions of children. We declare no competing interests. This work was supported by Danish Council for Independent Research (DFF-1333-00192), European Union FP7 support for OPTIMUNISE (grant Health F3-2011-261375). The Bandim Health Project received support from Danish National Research Foundation via support to CVIVA (grant: DNRF108). The funding agencies had no role in the writing of the correspondence or in the decision to submit the correspondence for publication.
*Stine Byberg, Ane Bærent Fisker [email protected] Bandim Health Project, INDEPTH network, Apartado 861, 1004 Bissau Codex, Guinea-Bissau (SB, ABF); Research Center for Vitamins and Vaccines (CVIVA), Statens Serum Institut, Copenhagen S, Denmark (SB, ABF); and OPEN, Odense Patient Data Explorative Network, Odense University Hospital/ Institute of Clinical Research, University of Southern Denmark, Odense, Denmark (SB) 1
2
3
4
5
6
Thompson KM. Good news for billions of children who will receive IPV. Lancet Infect Dis 2015; 15: 1120–22. Lund N, Andersen A, Hansen ASK, et al. The effect of oral polio vaccine at birth on infant mortality: a randomized trial. Clin Infect Dis 2015; 61: 1504–11. Higgins J, Soares-Weiser K, Reingold A. Systematic review of the non-specific effects of BCG, DTP and measles containing vaccines Geneva: World Health Organization, 2014. http://www.who.int/immunization/sage/ meetings/2014/april/3_NSE_Epidemiology_ review_Report_to_SAGE_14_Mar_FINAL. pdf?ua=1 (accessed Dec 12, 2015). Aaby P, Rodrigues A, Biai S, et al. Oral polio vaccination and low case fatality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine 2004; 22: 3014–17. Anon. Meeting of Global Advisory Committee on Vaccine Safety, June 18–19, 2008. Wkly Epidemiol Rec 2008; 83: 28–92. Aaby P, Garly ML, Nielsen J, et al. Increased female-male mortality ratio associated with inactivated polio and diphtheria-tetanuspertussis vaccines: observations from vaccination trials in Guinea-Bissau. Pediatr Infect Dis J 2007; 26: 247–52.
409
1
2
3
4
5
6
7
8
Horby PW, Endzt H, Muyembe-Tamfum JJ, et al. Ebola: Europe–Africa research collaborations. Lancet Infect Dis 2015; 15: 1258–59. Yazdanpanah Y, Horby P, van Griensven J, et al. Drug assessment in the Ebola virus disease epidemic in west Africa. Lancet Infect Dis 2015; 15: 1258. Lanini S, Zumla A, Ioannidis JP, et al. Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa? Lancet Infect Dis 2015; 15: 738–45. Ippolito G, Lanini S, Brouqui P, et al. Ebola: missed opportunities for Europe–Africa research. Lancet Infect Dis 2015; 15: 1254–55. Byar DP, Schoenfeld DA, Green SB, et al. Design considerations for AIDS trials. N Engl J Med 1990; 323: 1343–48. Cohen J, Enserink M. Infectious disease. As Ebola epidemic draws to a close, a thin scientific harvest. Science 2016; 351: 12–13. de Jong MD, Reusken C, Horby P, et al. Preparedness for admission of patients with suspected Ebola virus disease in European hospitals: a survey, August–September 2014. Euro Surveill 2014; 19: 20980. Ippolito G, Feldmann H, Lanini S, et al. Viral hemorrhagic fevers: advancing the level of treatment. BMC Med 2012; 10: 31.
BCG vaccination: a long-lasting protection against tuberculosis? The recent study by Patrick Nguipdop-Djomo and colleagues 1 showed that BCG vaccination conferred long-lasting protection against tuberculosis disease in a large tuberculin skin test (TST) negative population in Norway between 1962 and 1975. Tuberculosis rates were 3·3 per 100 000 person-years in BCG unvaccinated individuals and 1·3 per 100 000 person-years in BCG vaccinated individuals. This study echoes previous studies that BCGderived immunity persists longer than 10–15 years.2 The authors state “Prophylactic treat ment for latent tuberculosis infection was seldom used in Norway before 2002 and therefore was not a concern”, but would isoniazid prevention therapy prescribed from 2002 to 2011 explain the difference in tuberculosis rates if it was more 408
frequently prescribed to BCG vaccinated individuals? Preventive therapy with isoniazid with or without rifamycin can reduce the risk of future disease by 60–90%. 3 Furthermore, the analysis did not describe factors such as exposure to smear-positive cases in the BCG unvaccinated group, immigrants from countries with high tuberculosis burden, HIV positivity, malnutrition, diabetes, silicosis, injection drug abuse, homelessness, chronic renal failure/haemodialysis, gastrectomy, jejunoileal bypass, renal or cardiac transplantation, and carcinoma of the head or neck.4,5 One of the limitations of relying on administrative data might be incomplete risk factor information available for all 381 326 participants compared with that available from tuberculosis registries. It is important to determine whether there is a difference in risk factors rates by BCG vaccination status in the 260 people who developed tuberculosis. If any or some of the risk factors were more likely to be present in the BCG unvaccinated, the vaccine efficacy might have been overestimated. I declare no competing interests.
Eduardo Hernández-Garduño [email protected] Teaching and Research Department, Instituto de Seguridad Social del Estado de México y Municipios (ISSEMyM), Colonia del Parque, Toluca, Estado de México 50180, Mexico 1
2
3
4
5
Nguipdop-Djomo P, Heldal E, Rodrigues LC, et al. Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study. Lancet Infect Dis 2015; 16: 219–26. Aronson NE, Santosham M, Comstock GW, et al. Long-term efficacy of BCG vaccine in American Indians and Alaska natives: a 60-year follow-up study. JAMA 2004; 291: 2086–91. Leung CC, Rieder HL, Lange C, et al. Treatment of latent infection with Mycobacterium tuberculosis: update 2010. Eur Respir J 2011; 37: 690–711. Fox GJ, Barry SE, Britton WJ, Marks GB. Contact investigation for tuberculosis: a systematic review and meta-analysis. Eur Respir J 2013; 41: 140–56. Anon. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000; 49: 1–51.
Authors’ reply We thank Eduardo HernándezGarduño for his interest in our study.1 In his Correspondence, he wonders if differences in treatment for latent tuberculosis infection or other risk factors for tuberculosis in BCG vaccinated groups compared with unvaccinated groups—ie, confounding—could overestimate vaccine effectiveness against tuberculosis. Treatment for latent tuberculosis infection increased very little in the Norwegian-born population from 2002 to 2011, and there is no evidence or reason why prescriptions would differ by vaccination status. We also note that 2002–11 represent at most the past 9 years of the more than 40 years’ follow-up, and is thus unlikely to affect estimates of vaccine effectiveness early on. Furthermore, if BCG vaccination confers some protection against Mycobacterium tuberculosis infection as suggested by emerging evidence,2 then latent tuberculosis infection (and treatment) would be more frequent in the unvaccinated group, with the effect of underestimating rather than overestimating vaccine effectiveness against tuberculosis. It would have been interesting to compare some of the tuberculosis risk factors suggested in the letter between vaccination groups; unfortunately these data were unavailable. However, the distribution of socioeconomic indicators available, including educational attainment, occupation, as well as local tuberculosis rates did not vary much between BCG vaccine recipients and tuberculin-negative non-vaccinated individuals.1 These factors were also found to be only weak confounders in our analysis. HIV was not present in Norway at the start of this study, and the prevalence remains extremely low in the Norwegian-born population. Malnutrition does not seem to be relevant in this setting, and silicosis is rare. More generally, as acknowledged in our study, it is difficult to completely exclude the possibility of residual www.thelancet.com/infection Vol 16 April 2016
Correspondence
confounding in observational studies, be it from unmeasured or unknown confounders. However, in view of the widespread nature of the tuberculosis screening and BCG vaccination programme, it is likely that factors affecting delivery were more important than was individual predisposition to tuberculosis. It is thus unlikely that the distribution of other risk factors would vary very much between unvaccinated and vaccinated individuals after such screening and over the long followup period. Overall, as discussed in our study, it is more likely that our estimates of vaccine effectiveness of 49% (95% CI 26–65) over 40 years are conservative, in view of the characteristics of the study participants and the difficulty of excluding those with previous infection and sensitisation to environmental mycobacteria. LCR, PM, and IA are co-investigators in a separate study of a similar question in another setting (England) funded by a grant from the UK National Institute for Health Research during the conduct of this study. IA reports grants from the UK National Institute for Health Research and British Medical Research Council for other tuberculosis-related research during the conduct of this study. PN-D and EH declare no competing interests.
*Patrick Nguipdop-Djomo, Einar Heldal, Laura Cunha Rodrigues, Ibrahim Abubakar, Punam Mangtani [email protected] Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK 1
2
Nguipdop-Djomo P, Heldal E, Rodrigues LC, Abubakar I, Mangtani P. Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study. Lancet Infect Dis 2016; 16: 219–26. Roy A, Eisenhut M, Harris RJ, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ 2014; 349: g4643.
Is introduction of IPV “Good news for billions of children”? Mass worldwide vaccination with oral polio vaccine (OPV) has resulted in a steep decrease in polio infections and associated paralysis. Since the world www.thelancet.com/infection Vol 16 April 2016
is now close to eradicating polio, vaccine-derived polio constitutes an increasing proportion of overall polio infections. From this perspective, introduction of the more expensive inactivated polio vaccine (IPV) solves a problem as emphasised in the Comment by Kimberley Thompson.1 Passive reporting of adverse events in sequential cohorts could show whether any suspected side-effects suddenly increase with a change in vaccine use. However, it does not provide an overall assessment of whether the vaccine actually benefits the health of children. Studies from Guinea-Bissau have shown important beneficial effects of the OPV on child health: mortality was 32% (95% CI 0–55; HR 0·68 [95% CI 0·45–1·00]) lower among neonates randomly assigned to both OPV and BCG than among those randomly assigned to BCG only.2 Observational studies also support the beneficial non-specific effects of OPV on child mortality, reducing mortality by far more than can be explained by preventing polio infections alone. A recent review commissioned by WHO of the non-specific effects of the live measles and BCG vaccines and the inactivated diphtheria-tetanuspertussis (DTP) vaccine concluded that measles and BCG vaccines could reduce child mortality by up to 50%.3 For the DTP vaccine, most studies indicated a negative effect on child mortality.3 In developing countries, DTP and OPV are administered together; during the early 2000s shortages of DTP vaccine in Guinea-Bissau enabled a study of OPV only versus DTP and OPV coadministration. The hospital case-fatality rate was 0·29 (95% CI 0·11–0·77) for oral polio vaccine only compared with the reference (DTP plus OPV),4 suggesting that the OPV neutralises some of the detrimental effects of the DTP vaccine. In 2008, following the demonstration of methodological flaws in studies concluding that there was no sign of a negative effect of DTP, the Global Advisory Committee on Vaccine
Safety stated that it would monitor the evidence of non-specific effects of vaccines.5 It remains to be assessed whether IPV has non-specific effects and especially whether IPV could be detrimental for child health. IPV has been used as a comparator vaccine in randomised trials; girls randomly assigned to IPV had 52% (95% 2–128) higher mortality than did boys who were randomly assigned to the vaccine.6 Considering the beneficial effects of OPV, the effect on all-cause child mortality of replacing the OPV with the IPV in routine vaccination programmes should be assessed to ensure that it is in fact not bad news for billions of children. We declare no competing interests. This work was supported by Danish Council for Independent Research (DFF-1333-00192), European Union FP7 support for OPTIMUNISE (grant Health F3-2011-261375). The Bandim Health Project received support from Danish National Research Foundation via support to CVIVA (grant: DNRF108). The funding agencies had no role in the writing of the correspondence or in the decision to submit the correspondence for publication.
*Stine Byberg, Ane Bærent Fisker [email protected] Bandim Health Project, INDEPTH network, Apartado 861, 1004 Bissau Codex, Guinea-Bissau (SB, ABF); Research Center for Vitamins and Vaccines (CVIVA), Statens Serum Institut, Copenhagen S, Denmark (SB, ABF); and OPEN, Odense Patient Data Explorative Network, Odense University Hospital/ Institute of Clinical Research, University of Southern Denmark, Odense, Denmark (SB) 1
2
3
4
5
6
Thompson KM. Good news for billions of children who will receive IPV. Lancet Infect Dis 2015; 15: 1120–22. Lund N, Andersen A, Hansen ASK, et al. The effect of oral polio vaccine at birth on infant mortality: a randomized trial. Clin Infect Dis 2015; 61: 1504–11. Higgins J, Soares-Weiser K, Reingold A. Systematic review of the non-specific effects of BCG, DTP and measles containing vaccines Geneva: World Health Organization, 2014. http://www.who.int/immunization/sage/ meetings/2014/april/3_NSE_Epidemiology_ review_Report_to_SAGE_14_Mar_FINAL. pdf?ua=1 (accessed Dec 12, 2015). Aaby P, Rodrigues A, Biai S, et al. Oral polio vaccination and low case fatality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine 2004; 22: 3014–17. Anon. Meeting of Global Advisory Committee on Vaccine Safety, June 18–19, 2008. Wkly Epidemiol Rec 2008; 83: 28–92. Aaby P, Garly ML, Nielsen J, et al. Increased female-male mortality ratio associated with inactivated polio and diphtheria-tetanuspertussis vaccines: observations from vaccination trials in Guinea-Bissau. Pediatr Infect Dis J 2007; 26: 247–52.
409