- Email: [email protected]
Substantial benefits from finding the most effective BCG strain
Correspondence
Substantial benefits from finding the most effective BCG strain In their excellent commentary, Ben Marais and colleagues1 discuss the protection provided by BCG against tuberculosis, and its beneficial heterologous effects that reduce mortality from pneumonia and sepsis in children in low-income countries. Marais and colleagues 1 present important information about two new vaccines against Mycobacterium tuberculosis, but emphasise that introduction is likely to be many years away. The authors note that an unintended consequence of the expectation of new vaccines against M tuberculosis is a reluctance to invest in BCG production, but they do not mention another important consequence: a reluctance to determine the most effective strain of BCG. Different strains of BCG have very different effects on tuberculosis.2,3 A large randomised trial in 303 092 neonates in Hong Kong found that the risk of tuberculosis with BCG Pasteur vaccine was 45% (95% CI 22–61) less than with BCG Glaxo.3 Also, in a cohort study in Kazakhstan, vaccination of neonates reduced the risk of clinically diagnosed tuberculosis
by 69% (61–75) after BCG Tokyo, but by only 22% (7–35) after BCG Moscow.4 BCG Tokyo was three times as effective as BCG Moscow in Kazakhstan, but UNICEF supplied only 31 million doses of BCG Tokyo compared with 86 million doses of BCG Moscow worldwide in 2014.5 In addition to the important effects of genetic differences between strains of BCG, genetic heterogeneity within individual seed lots can cause major differences in BCG produced from the same seed lot by different manufacturers, and between different batches from a single manufacturer.2 For example, BCG Tokyo and BCG Danish each contain at least two genotypes. We could substantially improve the performance of BCG by comparing the individual genomes in BCG Tokyo, BCG Danish, and BCG Moscow to find which genome provides the best protection against tuberculosis and against pneumonia and sepsis.2 Comstock has suggested that protection against tuberculosis could be tested easily with an ABAB observational study.3 In such a study, all neonates in a defined region would be vaccinated with one strain (A) of BCG for a year and another strain (B) the next year, with the alternation continued for another 2 years (AB). Providing tuberculosis was recognised
similarly in odd and even years, this ingenious design would approach true randomisation, but at much lower cost. The most effective BCG genome could easily be identified at low cost. Routine use of this genome would substantially improve protection against tuberculosis and also enhance the heterologous effects of BCG that protect children in low-income countries against pneumonia and sepsis. I declare no competing interests.
Frank Shann [email protected] Department of Paediatrics, University of Melbourne, Parkville 3052, Australia 1
2
3
4
5
Marais BJ, Seddon JA, Detjen AK, et al. Interrupted BCG vaccination is a major threat to global child health. Lancet Respir Med 2016; 4: 251–53. Shann F. Different strains of Bacillus Calmette–Guérin vaccine have very different effects on tuberculosis and on unrelated infections. Clin Infect Dis 2015; 61: 960–62. Comstock GW. Simple, practical ways to assess the protective efficacy of a new tuberculosis vaccine. Clin Infect Dis Off Publ Infect Dis Soc Am 2000; 30 (suppl 3): S250–53. Favorov M, Ali M, Tursunbayeva A, et al. Comparative tuberculosis (TB) prevention effectiveness in children of Bacillus Calmette-Guérin (BCG) Vaccines from different sources, Kazakhstan. PLoS One 2012; 7: e32567. UNICEF Supply Division. BCG vaccine: current supply & demand outlook. www.unicef.org/ supply/files/BCG_Supply_Status_ December_2014.pdf (accessed April 28, 2016).
Corrections Storre JH. Non-invasive oxygenation strategies in hypoxaemic respiratory failure. Lancet Respir Med 2016; published online May 27. http://dx.doi. org/10.1016/S2213-2600(16)30139-4—The appendix linked to this Comment and the appendix citations in the text have now been included. These corrections have been made to the online version as of June 13, 2016 and will be made to the printed version.
www.thelancet.com/respiratory Vol 4 July 2016
Lancet Respir Med 2016 Published Online June 13, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30158-8
e35
Substantial benefits from finding the most effective BCG strain In their excellent commentary, Ben Marais and colleagues1 discuss the protection provided by BCG against tuberculosis, and its beneficial heterologous effects that reduce mortality from pneumonia and sepsis in children in low-income countries. Marais and colleagues 1 present important information about two new vaccines against Mycobacterium tuberculosis, but emphasise that introduction is likely to be many years away. The authors note that an unintended consequence of the expectation of new vaccines against M tuberculosis is a reluctance to invest in BCG production, but they do not mention another important consequence: a reluctance to determine the most effective strain of BCG. Different strains of BCG have very different effects on tuberculosis.2,3 A large randomised trial in 303 092 neonates in Hong Kong found that the risk of tuberculosis with BCG Pasteur vaccine was 45% (95% CI 22–61) less than with BCG Glaxo.3 Also, in a cohort study in Kazakhstan, vaccination of neonates reduced the risk of clinically diagnosed tuberculosis
by 69% (61–75) after BCG Tokyo, but by only 22% (7–35) after BCG Moscow.4 BCG Tokyo was three times as effective as BCG Moscow in Kazakhstan, but UNICEF supplied only 31 million doses of BCG Tokyo compared with 86 million doses of BCG Moscow worldwide in 2014.5 In addition to the important effects of genetic differences between strains of BCG, genetic heterogeneity within individual seed lots can cause major differences in BCG produced from the same seed lot by different manufacturers, and between different batches from a single manufacturer.2 For example, BCG Tokyo and BCG Danish each contain at least two genotypes. We could substantially improve the performance of BCG by comparing the individual genomes in BCG Tokyo, BCG Danish, and BCG Moscow to find which genome provides the best protection against tuberculosis and against pneumonia and sepsis.2 Comstock has suggested that protection against tuberculosis could be tested easily with an ABAB observational study.3 In such a study, all neonates in a defined region would be vaccinated with one strain (A) of BCG for a year and another strain (B) the next year, with the alternation continued for another 2 years (AB). Providing tuberculosis was recognised
similarly in odd and even years, this ingenious design would approach true randomisation, but at much lower cost. The most effective BCG genome could easily be identified at low cost. Routine use of this genome would substantially improve protection against tuberculosis and also enhance the heterologous effects of BCG that protect children in low-income countries against pneumonia and sepsis. I declare no competing interests.
Frank Shann [email protected] Department of Paediatrics, University of Melbourne, Parkville 3052, Australia 1
2
3
4
5
Marais BJ, Seddon JA, Detjen AK, et al. Interrupted BCG vaccination is a major threat to global child health. Lancet Respir Med 2016; 4: 251–53. Shann F. Different strains of Bacillus Calmette–Guérin vaccine have very different effects on tuberculosis and on unrelated infections. Clin Infect Dis 2015; 61: 960–62. Comstock GW. Simple, practical ways to assess the protective efficacy of a new tuberculosis vaccine. Clin Infect Dis Off Publ Infect Dis Soc Am 2000; 30 (suppl 3): S250–53. Favorov M, Ali M, Tursunbayeva A, et al. Comparative tuberculosis (TB) prevention effectiveness in children of Bacillus Calmette-Guérin (BCG) Vaccines from different sources, Kazakhstan. PLoS One 2012; 7: e32567. UNICEF Supply Division. BCG vaccine: current supply & demand outlook. www.unicef.org/ supply/files/BCG_Supply_Status_ December_2014.pdf (accessed April 28, 2016).
Corrections Storre JH. Non-invasive oxygenation strategies in hypoxaemic respiratory failure. Lancet Respir Med 2016; published online May 27. http://dx.doi. org/10.1016/S2213-2600(16)30139-4—The appendix linked to this Comment and the appendix citations in the text have now been included. These corrections have been made to the online version as of June 13, 2016 and will be made to the printed version.
www.thelancet.com/respiratory Vol 4 July 2016
Lancet Respir Med 2016 Published Online June 13, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30158-8
e35