Dr Yung claims that the evidence that vaccines have *any* “off target” effects is weak and vulnerable to biases. This is incorrect. BCG has a strong off-target effect against carcinoma of the bladder, and two randomised trials of BCG-Denmark in low birth weight infants were classified as having low risk of bias in the WHO-sponsored systematic review of vaccines by Higgins and colleagues (Higgins Review).[1] A third randomised trial has been published since, and the three trials combined show that BCG-Denmark reduces all-cause neonatal mortality by 38% (95% CI, 17% to 54%),[2] a spectacular reduction.
Dr Yung claims that it is beyond debate that diphtheria, tetanus and pertussis (DTP) vaccine is safe, and yet the Higgins Review found that DTP is associated with a 38% (-8% to 108%) increase in mortality – and with a 53% (2% to 130%) increase in mortality if the Papua New Guinea study with extreme survival and/or frailty bias is excluded, as recommended by 2 of the 3 peer reviewers.[3] This finding cannot be dismissed as being due to bias: first the main sources of bias in vaccine cohort studies, survival bias and frailty bias, make DTP look less harmful;[4] second, bias *cannot* explain why mortality is reduced by BCG at birth, then increased by DTP at 2-4 months, then reduced again by measles vaccine at 9 months within individual studies where there are the similar biases for all three vaccines (Higgins Review, Figure 8). Dr Yung points out that there are no randomised trials of the effect of DTP on all-cause mortality, which is precisely why a trial is urgently needed to demonstrate that DTP is safe (or not) – this could be done by randomising children to receive or not receive the booster dose of DTP in the second year of life, which many countries do not give even though it is recommended by WHO.
The findings of the WHO-sponsored Higgins Review are consistent with the hypothesis that, until a different vaccine is given, live vaccines (such as BCG and measles vaccine) *reduce* mortality from diseases other than the target disease, but that non-live vaccines (such as DTP) *increase* mortality from diseases other than the target disease.[5] The Figure shows a simplified version of the current WHO-recommended immunisation schedule (Schedule A), and a “live vaccine last” schedule modified so that a child’s most recent immunisation is with a live vaccine for as long as possible (Schedule B). The Higgins Review (Figure 5) suggests that giving BCG with DTP at 14 weeks (as in Schedule B) reduces mortality by 48% (100% - 52%) compared to giving DTP after BCG (as in the WHO-recommended Schedule A), and giving MV after DTP (as in Schedule B) reduces mortality by 62% (100% - 100%/2.66) compared to giving DTP after MV (as in the WHO-recommended Schedule A) .
Worldwide, excluding North America and Western Europe, in 2016 there were 2.641 million neonatal deaths, 1.672 million post-neonatal infant deaths (34,623 each week of age from 28 days to 366 days), and 1.282 million post-infant under-5 deaths (26,705 each month of age from 12 to 59.99 months).[6] If all children were immunised on schedule, compared to Schedule A (WHO-recommended), Schedule B (live-vaccine-last) would have 34,623 x 0.48 x 25.2 = 418,800 fewer deaths per year among children aged 14wk to 8.99mo (25.2wk), and 26,705 x 0.62 x 42 = 695,400 fewer deaths per year among children aged 18-59.99mo (42mo); 418,800 + 695,400 = 1,114,200 fewer deaths per year. Schedule B gives a second dose of BCG with the third priming dose of DTP at 14w of age, and omits the DTP booster at 18m of age – and would have approximately 1.1 million fewer under-5 deaths per year compared to the WHO-recommended Schedule A.
*****************************************************************************************************
Figure. A simplified version of the immunisation schedule recommended by WHO (Schedule A) and a “live-vaccine-last” schedule where a child's most recent immunisation is with a live vaccine for as long as possible (Schedule B).
1 Higgins JPT, Soares-Weiser K, López-López JA, et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 2016;355:i5170.
2 Biering-Sørensen S, Aaby P, Lund N, et al. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial. Clin Infect Dis 2017;65:1183–90. doi:10.1093/cid/cix525
3 Higgins J. Re: Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ Published Online First: 27 February 2017. http://www.bmj.com/content/355/bmj.i5170/rr-7 (accessed 23 Aug 2018).
4 Aaby P, Ravn H, Benn CS. The WHO Review of the Possible Non-Specific Effects of Diphtheria-Tetanus-Pertussis Vaccine. Pediatr Infect Dis J 2016;35:1247–57.
5 Shann F. The heterologous (non-specific) effects of vaccines: implications for policy in high-mortality countries. Trans R Soc Trop Med Hyg 2015;109:5–8. doi:10.1093/trstmh/tru161
6 UNICEF. The State of the World’s Children 2017. UNICEF. 2017.https://www.unicef.org/sowc2017/ (accessed 23 Aug 2018).
Competing interests:
No competing interests
23 August 2018
Frank Shann
Professorial Fellow
Department of Paediatrics
University of Melbourne, Parkville, Victoria 3052, Australia
Rapid Response:
Re: Non-specific effects of childhood vaccines
Dr Yung claims that the evidence that vaccines have *any* “off target” effects is weak and vulnerable to biases. This is incorrect. BCG has a strong off-target effect against carcinoma of the bladder, and two randomised trials of BCG-Denmark in low birth weight infants were classified as having low risk of bias in the WHO-sponsored systematic review of vaccines by Higgins and colleagues (Higgins Review).[1] A third randomised trial has been published since, and the three trials combined show that BCG-Denmark reduces all-cause neonatal mortality by 38% (95% CI, 17% to 54%),[2] a spectacular reduction.
Dr Yung claims that it is beyond debate that diphtheria, tetanus and pertussis (DTP) vaccine is safe, and yet the Higgins Review found that DTP is associated with a 38% (-8% to 108%) increase in mortality – and with a 53% (2% to 130%) increase in mortality if the Papua New Guinea study with extreme survival and/or frailty bias is excluded, as recommended by 2 of the 3 peer reviewers.[3] This finding cannot be dismissed as being due to bias: first the main sources of bias in vaccine cohort studies, survival bias and frailty bias, make DTP look less harmful;[4] second, bias *cannot* explain why mortality is reduced by BCG at birth, then increased by DTP at 2-4 months, then reduced again by measles vaccine at 9 months within individual studies where there are the similar biases for all three vaccines (Higgins Review, Figure 8). Dr Yung points out that there are no randomised trials of the effect of DTP on all-cause mortality, which is precisely why a trial is urgently needed to demonstrate that DTP is safe (or not) – this could be done by randomising children to receive or not receive the booster dose of DTP in the second year of life, which many countries do not give even though it is recommended by WHO.
The findings of the WHO-sponsored Higgins Review are consistent with the hypothesis that, until a different vaccine is given, live vaccines (such as BCG and measles vaccine) *reduce* mortality from diseases other than the target disease, but that non-live vaccines (such as DTP) *increase* mortality from diseases other than the target disease.[5] The Figure shows a simplified version of the current WHO-recommended immunisation schedule (Schedule A), and a “live vaccine last” schedule modified so that a child’s most recent immunisation is with a live vaccine for as long as possible (Schedule B). The Higgins Review (Figure 5) suggests that giving BCG with DTP at 14 weeks (as in Schedule B) reduces mortality by 48% (100% - 52%) compared to giving DTP after BCG (as in the WHO-recommended Schedule A), and giving MV after DTP (as in Schedule B) reduces mortality by 62% (100% - 100%/2.66) compared to giving DTP after MV (as in the WHO-recommended Schedule A) .
Worldwide, excluding North America and Western Europe, in 2016 there were 2.641 million neonatal deaths, 1.672 million post-neonatal infant deaths (34,623 each week of age from 28 days to 366 days), and 1.282 million post-infant under-5 deaths (26,705 each month of age from 12 to 59.99 months).[6] If all children were immunised on schedule, compared to Schedule A (WHO-recommended), Schedule B (live-vaccine-last) would have 34,623 x 0.48 x 25.2 = 418,800 fewer deaths per year among children aged 14wk to 8.99mo (25.2wk), and 26,705 x 0.62 x 42 = 695,400 fewer deaths per year among children aged 18-59.99mo (42mo); 418,800 + 695,400 = 1,114,200 fewer deaths per year. Schedule B gives a second dose of BCG with the third priming dose of DTP at 14w of age, and omits the DTP booster at 18m of age – and would have approximately 1.1 million fewer under-5 deaths per year compared to the WHO-recommended Schedule A.
*****************************************************************************************************
Figure. A simplified version of the immunisation schedule recommended by WHO (Schedule A) and a “live-vaccine-last” schedule where a child's most recent immunisation is with a live vaccine for as long as possible (Schedule B).
SCHEDULE A: 0wk BCG; 6wk, 10wk, 14wk DTP; 9mo MV; 18mo DTP + MV
SCHEDULE B: 0wk BCG; 6,10wk DTP; 14wk DTP+BCG; 9mo MV; 18mo MV
BCG = BCG-Denmark + OPV; DTP = DTP-containing vaccines; MV = EZ MV (or MMR ± YF).
*****************************************************************************************************
1 Higgins JPT, Soares-Weiser K, López-López JA, et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 2016;355:i5170.
2 Biering-Sørensen S, Aaby P, Lund N, et al. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial. Clin Infect Dis 2017;65:1183–90. doi:10.1093/cid/cix525
3 Higgins J. Re: Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ Published Online First: 27 February 2017. http://www.bmj.com/content/355/bmj.i5170/rr-7 (accessed 23 Aug 2018).
4 Aaby P, Ravn H, Benn CS. The WHO Review of the Possible Non-Specific Effects of Diphtheria-Tetanus-Pertussis Vaccine. Pediatr Infect Dis J 2016;35:1247–57.
5 Shann F. The heterologous (non-specific) effects of vaccines: implications for policy in high-mortality countries. Trans R Soc Trop Med Hyg 2015;109:5–8. doi:10.1093/trstmh/tru161
6 UNICEF. The State of the World’s Children 2017. UNICEF. 2017.https://www.unicef.org/sowc2017/ (accessed 23 Aug 2018).
Competing interests: No competing interests