Vaccine 32 (2014) 2668–2669
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Reply to Letter to the Editor
Reply to Dr Schmid et al. We thank Dr Schmid and colleagues for their comments on our paper. Dr Schmid and colleagues rightly point out that we have not assessed whether each individual death could be classified as a causal event using the algorithm developed by the Clinical Immunization Safety Assessment network [1]. However, the algorithm only deals with adverse events caused directly by vaccination, one of the criteria for example being that a vaccine component is identified in the pathogenesis [1]. It does not deal with the non-specific/heterologous effects of vaccines which alter the susceptibility to unrelated pathogens [2]. Hence most deaths in our study are likely not causal using the algorithm, but this does not rule out that the vaccine altered susceptibility to the pathogen which caused the death. Dr Schmid et al. also caution against interpreting our results as evidence for the existence of non-specific negative effects of the DTP-containing vaccines. We agree that the observational nature of our study calls for a cautious interpretation, our sample was small, and adjustment for many background factors could provide unstable results. However, using a propensity score analysis did not change the conclusions and hence we do not think this is the case. Dr Schmid refers to the Global Advisory Committee on Vaccine Safety (GACVS) statement from 2008 that “conclusive evidence is not likely to be obtained from observational studies”. However, the GACVS statement continues: “The GACVS will keep a watch on the evidence of non-specific effects of vaccination” [3]. The million dollar question is how to do that? The vaccines used in the present vaccination programme have been in use for decades without ever being tested in randomised trials for their overall effect on child health. Randomised trials of vaccines used in the vaccination programmes are usually perceived as unethical since it would imply depriving some children of a vaccination they would otherwise have received. Hence, public health professionals, vaccine producers and policy makers have little other choice than attempting to assess evidence of benefits or harm from observational studies – of course interpreted with appropriate caution. Dr Schmid and colleagues refer to “biases resulting from methodological and analytical issues” as explaining the conflicting results of the prior studies of the non-specific effects of DTPcontaining vaccines. These conflicting results have occurred when the vaccination status of children is assessed through inspection of vaccination cards seen during home visits and different analytical
DOI of original article: http://dx.doi.org/10.1016/j.vaccine.2014.03.034. http://dx.doi.org/10.1016/j.vaccine.2014.03.060 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
approaches have been applied. For instance, if a child is allowed to contribute time in the vaccinated group from the date of vaccination (retrospective update), rather than the date of the home visit (landmark approach) time in the vaccinated group is inflated [4] and studies using the retrospective update approach have invariably found very beneficial effects of all vaccines [5]. In the present study the vaccines were administered by our staff, and hence there was no misclassification of the exposure or the observation time. Other types of bias could still be present. An observational vaccine study with self-selection to vaccination is often biased towards a beneficial effect of any vaccine, since it is the healthier children with educated mothers and good access to health facilities who are vaccinated first [6]. Hence, observational studies which show a beneficial effect of a vaccine should obviously be interpreted in that light. However, any observational study finding a negative effect of a vaccine, in particular in a setting where other vaccines have positive effects, should call for attention. In the present study it could be claimed that the children who received simultaneous measles vaccine and DTP-containing vaccines were delayed in their vaccination schedule and therefore represent a special group with higher mortality. However, our adjusted analyses indicate that socio-economic and health-related selection biases explained only a small fraction of the difference in mortality. It should also be noted that the observed negative effect was stronger under the new vaccination programme and in the rural area when the baseline differences in socio-economic and nutritional status were small. Thus the results add to an accumulating body of evidence indicating that DTP-containing vaccines have effects beyond inducing protection against diphtheria, tetanus and pertussis [7]. References [1] Halsey NA, Edwards KM, Dekker CL, Klein NP, Baxter R, Larussa P, et al. Algorithm to assess causality after individual adverse events following immunizations. Vaccine 2012;30:5791–8. [2] Benn CS, Netea MG, Selin LK, Aaby P. A small jab – a big effect: nonspecific immunomodulation by vaccines. Trends Immunol 2013;34: 431–9. [3] Meeting of Global Advisory Committee on Vaccine Safety. Wkly Epidemiol Rec 2008;83:287–92. [4] Jensen H, Benn CS, Lisse IM, Rodrigues A, Andersen PK, Aaby P. Survival bias in observational studies of the impact of routine immunizations on childhood survival. Trop Med Int Health 2007;12:5–14. [5] Aaby P, Benn CS, Nielsen J, Lisse IM, Rodrigues A, Jensen H. DTP vaccination and child survival in observational studies with incomplete vaccination data. Trop Med Int Health 2007;12:15–24. [6] Aaby P, Ravn H, Roth A, Rodrigues A, Lisse IM, Diness BR, et al. Early diphtheriatetanus-pertussis vaccination associated with higher female mortality and no
Reply to Letter to the Editor / Vaccine 32 (2014) 2668–2669 difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial. Arch Dis Child 2012;97:685–91. [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:e000707.
Ane Bærent Fisker Christine Stabell Benn
2669
Henrik Ravn Peter Aaby Bandim Health Project, Guinea-Bissau and Research Center for Vaccines and Vitamins (CVIVA), Statens Serum Institut, Denmark E-mail address: a.fi[email protected] (A.B. Fisker) Available online 1 April 2014
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Reply to Letter to the Editor
Reply to Dr Schmid et al. We thank Dr Schmid and colleagues for their comments on our paper. Dr Schmid and colleagues rightly point out that we have not assessed whether each individual death could be classified as a causal event using the algorithm developed by the Clinical Immunization Safety Assessment network [1]. However, the algorithm only deals with adverse events caused directly by vaccination, one of the criteria for example being that a vaccine component is identified in the pathogenesis [1]. It does not deal with the non-specific/heterologous effects of vaccines which alter the susceptibility to unrelated pathogens [2]. Hence most deaths in our study are likely not causal using the algorithm, but this does not rule out that the vaccine altered susceptibility to the pathogen which caused the death. Dr Schmid et al. also caution against interpreting our results as evidence for the existence of non-specific negative effects of the DTP-containing vaccines. We agree that the observational nature of our study calls for a cautious interpretation, our sample was small, and adjustment for many background factors could provide unstable results. However, using a propensity score analysis did not change the conclusions and hence we do not think this is the case. Dr Schmid refers to the Global Advisory Committee on Vaccine Safety (GACVS) statement from 2008 that “conclusive evidence is not likely to be obtained from observational studies”. However, the GACVS statement continues: “The GACVS will keep a watch on the evidence of non-specific effects of vaccination” [3]. The million dollar question is how to do that? The vaccines used in the present vaccination programme have been in use for decades without ever being tested in randomised trials for their overall effect on child health. Randomised trials of vaccines used in the vaccination programmes are usually perceived as unethical since it would imply depriving some children of a vaccination they would otherwise have received. Hence, public health professionals, vaccine producers and policy makers have little other choice than attempting to assess evidence of benefits or harm from observational studies – of course interpreted with appropriate caution. Dr Schmid and colleagues refer to “biases resulting from methodological and analytical issues” as explaining the conflicting results of the prior studies of the non-specific effects of DTPcontaining vaccines. These conflicting results have occurred when the vaccination status of children is assessed through inspection of vaccination cards seen during home visits and different analytical
DOI of original article: http://dx.doi.org/10.1016/j.vaccine.2014.03.034. http://dx.doi.org/10.1016/j.vaccine.2014.03.060 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
approaches have been applied. For instance, if a child is allowed to contribute time in the vaccinated group from the date of vaccination (retrospective update), rather than the date of the home visit (landmark approach) time in the vaccinated group is inflated [4] and studies using the retrospective update approach have invariably found very beneficial effects of all vaccines [5]. In the present study the vaccines were administered by our staff, and hence there was no misclassification of the exposure or the observation time. Other types of bias could still be present. An observational vaccine study with self-selection to vaccination is often biased towards a beneficial effect of any vaccine, since it is the healthier children with educated mothers and good access to health facilities who are vaccinated first [6]. Hence, observational studies which show a beneficial effect of a vaccine should obviously be interpreted in that light. However, any observational study finding a negative effect of a vaccine, in particular in a setting where other vaccines have positive effects, should call for attention. In the present study it could be claimed that the children who received simultaneous measles vaccine and DTP-containing vaccines were delayed in their vaccination schedule and therefore represent a special group with higher mortality. However, our adjusted analyses indicate that socio-economic and health-related selection biases explained only a small fraction of the difference in mortality. It should also be noted that the observed negative effect was stronger under the new vaccination programme and in the rural area when the baseline differences in socio-economic and nutritional status were small. Thus the results add to an accumulating body of evidence indicating that DTP-containing vaccines have effects beyond inducing protection against diphtheria, tetanus and pertussis [7]. References [1] Halsey NA, Edwards KM, Dekker CL, Klein NP, Baxter R, Larussa P, et al. Algorithm to assess causality after individual adverse events following immunizations. Vaccine 2012;30:5791–8. [2] Benn CS, Netea MG, Selin LK, Aaby P. A small jab – a big effect: nonspecific immunomodulation by vaccines. Trends Immunol 2013;34: 431–9. [3] Meeting of Global Advisory Committee on Vaccine Safety. Wkly Epidemiol Rec 2008;83:287–92. [4] Jensen H, Benn CS, Lisse IM, Rodrigues A, Andersen PK, Aaby P. Survival bias in observational studies of the impact of routine immunizations on childhood survival. Trop Med Int Health 2007;12:5–14. [5] Aaby P, Benn CS, Nielsen J, Lisse IM, Rodrigues A, Jensen H. DTP vaccination and child survival in observational studies with incomplete vaccination data. Trop Med Int Health 2007;12:15–24. [6] Aaby P, Ravn H, Roth A, Rodrigues A, Lisse IM, Diness BR, et al. Early diphtheriatetanus-pertussis vaccination associated with higher female mortality and no
Reply to Letter to the Editor / Vaccine 32 (2014) 2668–2669 difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial. Arch Dis Child 2012;97:685–91. [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:e000707.
Ane Bærent Fisker Christine Stabell Benn
2669
Henrik Ravn Peter Aaby Bandim Health Project, Guinea-Bissau and Research Center for Vaccines and Vitamins (CVIVA), Statens Serum Institut, Denmark E-mail address: a.fi[email protected] (A.B. Fisker) Available online 1 April 2014
