Re: Is the timing of recommended childhood vaccines evidence based?
Rather than asking whether there is evidence that the timing of the vaccination programme prevents the targeted diseases, the question should be whether the timing of the programme optimises the impact of vaccines on child health.
That evidence base is insufficient. In low-income countries, where the burden of child mortality lies, the vaccines at the core of the Expanded Programme on Immunization (EPI) were not evaluated for their effect on child mortality before being introduced. An accumulating number of studies have now shown that the four core vaccines of the EPI, the Bacillus Calmette-Guerin vaccine (BCG, against tuberculosis), the diphtheria-tetanus-pertussis vaccine (DTP), the oral polio vaccine (OPV) and the measles vaccine (MV) all have effects on child health beyond their effect due to specific disease protection; i.e., the vaccines have non-specific effects (NSEs)[1]. These effects are strongest as long as a given vaccine is the most recent vaccine.
The studies have mostly been observational, since it is difficult to conduct randomised trials of already recommended vaccines. However, where feasible, randomised trials have supported the conclusions from observational studies by showing that the live attenuated vaccines BCG vaccine[2 3], OPV[4] and MV[5 6] are associated with lower mortality than predicted by the prevention of the target infections, i.e. these vaccines have beneficial NSEs. In contrast, DTP vaccine is associated with increased female mortality, in spite of protecting against the target infections[7].
These NSEs, however, have not been taken into consideration in the timing of vaccinations. For instance, all available data show that a policy of providing an additional early dose of MV shortly after DTP, to abrogate the negative mortality effect of DTP, would reduce mortality[5]. Also, in countries which use booster-DTP, a revaccination with BCG one month after booster-DTP may be very beneficial[8].
Both the “yes” and “no” side state that the time for randomised trials has passed, as it is not ethical to deprive children of a vaccine which is part of the recommended schedule[9]. The Strategic Advisory Group of Experts on Immunization (SAGE) recently reviewed the evidence for the NSEs of BCG, DTP and MV on all-cause child mortality[10]. Based on a literature review which found evidence of a beneficial effect of BCG and MV, but not for DTP (“the majority of the studies indicating a detrimental effect”)[11], SAGE has recommended further research and where possible randomised trials[10].
With the limited evidence behind the current timing, and an increasing amount of evidence documenting that changes to the current schedule may improve child health, there should be equipoise for studies evaluating alternatives to the current timing.
References
1. Benn CS, Netea MG, Selin LK, Aaby P. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends in immunology 2013;34(9):431-9 doi: 10.1016/j.it.2013.04.004.
2. Aaby P, Roth A, Ravn H, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011;204(2):245-52 doi: 10.1093/infdis/jir240.
3. Biering-Sorensen S, Aaby P, Napirna BM, et al. Small Randomized Trial Among Low-birth-weight Children Receiving Bacillus Calmette-Gueerin Vaccination at First Health Center Contact. Pediatr Infect Dis J 2012;31(3):306-8 doi: 10.1097/INF.0b013e3182458289.
4. Lund N, Andersen A, Hansen AS, et al. The Effect of Oral Polio Vaccine at Birth on Infant Mortality: A Randomized Trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2015;61(10):1504-11 doi: 10.1093/cid/civ617.
5. Aaby P, Martins CL, Garly ML, et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ 2010;341:c6495 doi: 10.1136/bmj.c6495.
6. Aaby P, Garly ML, Bale C, et al. Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study. Pediatr Infect Dis J 2003;22(9):798-805 doi: 10.1097/01.inf.0000083821.33187.b5.
7. Aaby P, Benn C, Nielsen J, Lisse IM, Rodrigues A, Ravn H. Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ open 2012;2(3):e000707 doi: 10.1136/bmjopen-2011-000707.
8. Roth AE, Benn CS, Ravn H, et al. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau. BMJ 2010;340:c671
9. Edwards KM, Maldonado Y, Byington CL, Jefferson T, Demicheli V. Is the timing of recommended childhood vaccines evidence based? BMJ 2016;352:i867 doi: 10.1136/bmj.i867.
10. World Health Organization. Meeting of the Strategic Advisory Group of Experts on immunization, April 2014 -- conclusions and recommendations. Wkly Epidemiol Rec 2014;89(21):221-36
11. Higgins JPT, Soares-Weiser K, Reingold A. Systematic review of the non-specific effects of BCG, DTP and measles containing vaccines. Available at: http://www.who.int/immunization/sage/meetings/2014/april/3_NSE_Epidemiol..., 2014.
Competing interests:
No competing interests
27 February 2016
Ane B Fisker
Post doc
Bandim Health Project, Guinea-Bissau and Research Center for Vitamins and Vaccines (CVIVA), Statens Serum Institut
Rapid Response:
Re: Is the timing of recommended childhood vaccines evidence based?
Rather than asking whether there is evidence that the timing of the vaccination programme prevents the targeted diseases, the question should be whether the timing of the programme optimises the impact of vaccines on child health.
That evidence base is insufficient. In low-income countries, where the burden of child mortality lies, the vaccines at the core of the Expanded Programme on Immunization (EPI) were not evaluated for their effect on child mortality before being introduced. An accumulating number of studies have now shown that the four core vaccines of the EPI, the Bacillus Calmette-Guerin vaccine (BCG, against tuberculosis), the diphtheria-tetanus-pertussis vaccine (DTP), the oral polio vaccine (OPV) and the measles vaccine (MV) all have effects on child health beyond their effect due to specific disease protection; i.e., the vaccines have non-specific effects (NSEs)[1]. These effects are strongest as long as a given vaccine is the most recent vaccine.
The studies have mostly been observational, since it is difficult to conduct randomised trials of already recommended vaccines. However, where feasible, randomised trials have supported the conclusions from observational studies by showing that the live attenuated vaccines BCG vaccine[2 3], OPV[4] and MV[5 6] are associated with lower mortality than predicted by the prevention of the target infections, i.e. these vaccines have beneficial NSEs. In contrast, DTP vaccine is associated with increased female mortality, in spite of protecting against the target infections[7].
These NSEs, however, have not been taken into consideration in the timing of vaccinations. For instance, all available data show that a policy of providing an additional early dose of MV shortly after DTP, to abrogate the negative mortality effect of DTP, would reduce mortality[5]. Also, in countries which use booster-DTP, a revaccination with BCG one month after booster-DTP may be very beneficial[8].
Both the “yes” and “no” side state that the time for randomised trials has passed, as it is not ethical to deprive children of a vaccine which is part of the recommended schedule[9]. The Strategic Advisory Group of Experts on Immunization (SAGE) recently reviewed the evidence for the NSEs of BCG, DTP and MV on all-cause child mortality[10]. Based on a literature review which found evidence of a beneficial effect of BCG and MV, but not for DTP (“the majority of the studies indicating a detrimental effect”)[11], SAGE has recommended further research and where possible randomised trials[10].
With the limited evidence behind the current timing, and an increasing amount of evidence documenting that changes to the current schedule may improve child health, there should be equipoise for studies evaluating alternatives to the current timing.
References
1. Benn CS, Netea MG, Selin LK, Aaby P. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends in immunology 2013;34(9):431-9 doi: 10.1016/j.it.2013.04.004.
2. Aaby P, Roth A, Ravn H, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011;204(2):245-52 doi: 10.1093/infdis/jir240.
3. Biering-Sorensen S, Aaby P, Napirna BM, et al. Small Randomized Trial Among Low-birth-weight Children Receiving Bacillus Calmette-Gueerin Vaccination at First Health Center Contact. Pediatr Infect Dis J 2012;31(3):306-8 doi: 10.1097/INF.0b013e3182458289.
4. Lund N, Andersen A, Hansen AS, et al. The Effect of Oral Polio Vaccine at Birth on Infant Mortality: A Randomized Trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2015;61(10):1504-11 doi: 10.1093/cid/civ617.
5. Aaby P, Martins CL, Garly ML, et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ 2010;341:c6495 doi: 10.1136/bmj.c6495.
6. Aaby P, Garly ML, Bale C, et al. Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study. Pediatr Infect Dis J 2003;22(9):798-805 doi: 10.1097/01.inf.0000083821.33187.b5.
7. Aaby P, Benn C, Nielsen J, Lisse IM, Rodrigues A, Ravn H. Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ open 2012;2(3):e000707 doi: 10.1136/bmjopen-2011-000707.
8. Roth AE, Benn CS, Ravn H, et al. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau. BMJ 2010;340:c671
9. Edwards KM, Maldonado Y, Byington CL, Jefferson T, Demicheli V. Is the timing of recommended childhood vaccines evidence based? BMJ 2016;352:i867 doi: 10.1136/bmj.i867.
10. World Health Organization. Meeting of the Strategic Advisory Group of Experts on immunization, April 2014 -- conclusions and recommendations. Wkly Epidemiol Rec 2014;89(21):221-36
11. Higgins JPT, Soares-Weiser K, Reingold A. Systematic review of the non-specific effects of BCG, DTP and measles containing vaccines. Available at: http://www.who.int/immunization/sage/meetings/2014/april/3_NSE_Epidemiol..., 2014.
Competing interests: No competing interests