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Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries

Background Measles vaccines (MV) have sex-differential effects on mortality not explained by protection against measles infection. Objective The authors examined whether whole-cell diphtheria–tetanus–pertussis (DTP) vaccine has sex-differential and non-specific effects. Data sources and eligibility Following previous reviews and a new search, the effect of DTP on mortality up to the next vaccination was assessed in all studies where DTP was given after BCG or DTP was given after MV and there was prospective follow-up after ascertainment of vaccination status. Setting High-mortality countries in Africa and Asia. Methods The initial observation of negative effect of DTP generated six hypotheses, which were examined in all available studies and two randomised trials reducing the time of exposure to DTP. Main outcome Consistency between studies. Results In the first study, DTP had negative effects on survival in contrast to the beneficial effects of BCG and MV. This pattern was repeated in the six other studies available. Second, the two ‘natural experiments’ found significantly higher mortality for DTP-vaccinated compared with DTP-unvaccinated children. Third, the female–male mortality ratio was increased after DTP in all nine studies; in contrast, the ratio was decreased after BCG and MV in all studies. Fourth, the increased female mortality associated with high-titre measles vaccine was found only among children who had received DTP after high-titre measles vaccine. Fifth, in six randomised trials of early MV, female but not male mortality was increased if DTP was likely to be given after MV. Sixth, the mortality rate declined markedly for girls but not for boys when DTP-vaccinated children received MV. The authors reduced exposure to DTP as most recent vaccination by administering a live vaccine (MV and BCG) shortly after DTP. Both trials reduced child mortality. Conclusions These observations are incompatible with DTP merely protecting against the targeted diseases. With herd immunity to whooping cough, DTP is associated with higher mortality for girls. Randomised studies of DTP are warranted to measure the true impact on survival.


Supplementary table 2: Mortality ratios for different routine vaccinations within the same study (Observation I) Study (ref)
Length of followup in study Mortality rates per 1000 person-years or case fatalities (%) and mortality ratios (

Appendix: Analysis of incomplete vaccination data
In the analysis of vaccination data, the completeness of the data and the mode of analysis as well as the study designs and associated biases have been critically important (113,114). The way data on vaccinations is collected in low-income countries has implications for the analysis. Data on vaccinations will most often be incomplete. In longitudinal studies, information on vaccination status has typically been collected at home visits with a certain interval between visits, for example, 1, 3, 6 or even 12 months. It is unlikely that information is obtained for all children and some vaccinations administered between visits will not be known. A few projects have provided all vaccinations for a certain period or collected information from the health centres (18,44,46,48,53) but few have successfully collected information from all children, including those who travelled or died (31). The one exception would be a recent study from Cebu, The Philippines, which collected post-mortem vaccination information from 99% of the children who died (58). As many mothers in Africa will throw away the vaccination card or move from the area if a child dies, information on vaccinations is likely to be better for children who survive.
Few studies excluded the children with "no information", instead these children were usually assumed to be unvaccinated controls (60,61). Hence, controls will include absent children who may be absent because they are sick or travelling, and this group may therefore be a high-risk group with a particularly high mortality (Table 1). For example, in one study from Malawi, the estimated impact of DTP1 on mortality changed from 0.99 to 3.19 when the comparison was restricted to unvaccinated children present in the community (53). Furthermore, such controls are likely to include children who would not have been included in a randomised clinical trial (RCT) due to chronic disease or malformation.

Retrospective updating and landmark approaches.
Methodological issues because of incomplete vaccination data are discussed in detail elsewhere (60)(61)(62)(63)113,114). In brief, when incomplete data are analysed with retrospective updating of vaccination status as a time-varying covariate, survival bias is introduced because information is better for surviving children. Some dead vaccinated children will be misclassified as unvaccinated giving a high mortality rate in the unvaccinated group. This will exaggerate the estimated survival benefit of vaccinations (60). For these reasons (60), we did not include studies with retrospective updating in the present examination of mortality levels after DTP (Table 1); these studies are reviewed elsewhere (61).
To avoid survival bias, vaccination dates should only be taken into consideration from the date they were registered. The status as "not vaccinated" should be based on assessment; "no information" should not be interpreted as "not vaccinated". These restrictions lead to a landmark approach (60) in which vaccination status is a fixed covariate for the period of follow-up. In other words, mortality is analysed from the date of data collection until the next time vaccination data are collected, disregarding vaccinations given during follow-up. The landmark approach is not affected by survival bias, though misclassification of vaccination status due to new vaccinations during follow-up may be important as discussed below. Most recent vaccination. The relevance of data analysed with the landmark approach depends on how many children might have received other vaccinations during follow-up; the unvaccinated group may receive the vaccine being examined and the vaccinated group may receive a subsequent vaccination during follow-up. If the unvaccinated and vaccinated groups receive only the examined vaccine, say further doses of DTP, the estimates of the effect of DTP vaccine on mortality will be conservative, i.e. biased towards 1.0 (1, 60). However, if alternative vaccines are also given, the resulting bias is unpredictable depending on the effect of the additional vaccines on mortality. We therefore emphasised periods in which additional vaccinations are unlikely. Hence, we are ideally analysing the effect of a specific vaccine in the restricted period in which it is the "most recent vaccination".

Study design issues
We have mostly used two lines of enquiries to examine the possible non-specific effects of DTP. These approaches are associated with very different biases. Comparison of sequential vaccinations. We compared DTP-vaccinated versus DTPunvaccinated children, i.e. totally unvaccinated or BCG-only vaccinated children. This comparison is inherently biased since vaccination statuses which are scheduled to be sequential are compared at the same age in a survival analysis. The selective factors which determine which children are vaccinated first are therefore critically important for what is being compared. It has been suggested several times that the weakest children are vaccinated first, because they got vaccinated when consulting at a health centre (18,45,48). The estimated effect of the most recent vaccination might therefore be negative. However, there is no well documented case of weak children being vaccinated first. Instead, most studies, including those from Guinea-Bissau, have found that vaccinated children have better nutritional status and that children with better nutritional status are vaccinated first (1,19,53,64). Furthermore, all studies suggest that vaccination coverage is associated with better maternal education (1,44,49,58), which is associated with better survival. Hence, all the current evidence suggests that low-risk children are vaccinated first, and the weak or "frail" children get delayed vaccination or no vaccination (63). This bias, which we call frailty bias, would leave the weak children to die in the unvaccinated or current-vaccination group, while moving the follow-up time for the low-risk children to the group of the next vaccination (58,59). The longer the comparison is extended the more the previous-vaccination group will consist of frail children, and the more biased the comparison will be (59). In situations with high vaccination coverage, comparison of BCGvaccinated versus unvaccinated, DTP versus BCG, or MV versus DTP, can only be conducted over a short age range (44,59). Frailty bias would tend to bias the estimates of the effect of all vaccines on mortality towards zero, i.e. better than the true effect.
Comparison of sequential vaccinations in a survival analysis would therefore inherently tend to provide a beneficial survival estimate for the most recent vaccinations even in the absence of any impact on survival. Such comparisons are therefore only informative when they provide an unexpected negative estimate for a specific vaccine, or contrasting estimates for different vaccines (1,64). Contrasting effects of different vaccines are an indication of non-specific effects unless it can be shown that different forms of selection or frailty bias are important for different vaccines. The available evidence suggests that these determinants are the same for different vaccines.
In comparisons of sequential vaccinations, the healthy newly-vaccinated children are compared with the weak not-yet vaccinated children at a specific age. Such frailty bias is not controlled by adjusting for common determinants of mortality level (maternal education, socio-economic status). Frailty bias is only fully controlled in randomised studies (82). Since randomised studies are not currently acceptable, we might seek "natural experiments" with limited self-selection for vaccination, for example, when vaccines were missing during a certain period (43), vaccines were only available in a certain period (37), or vaccines were stopped due to a war (21, 26). In such situations, vaccinated and unvaccinated children may be compared as they would in a randomised trial without the unvaccinated children being inherently more frail. However, such "natural experiments" with DTP are rare (42, 43).

Comparison of female and male mortality rates.
In the pre-vaccination era, post-neonatal child mortality was similar for boys and girls in Africa ( Figure 2). All data from Africa also suggest that girls and boys are treated equally with respect to vaccination and the age of vaccination, and that the coverage is the same for boys and girls. In these circumstances, a deviation of the female-male mortality rate ratio (MRR) from 1.0 for children who have received a specific vaccine as the most recent vaccination would suggest that this vaccine is associated with sexdifferential non-specific effects. We therefore conducted several studies examining the femalemale MRR. It should be noted that a comparison of female-male mortality rates is not affected by the same survival, selection and frailty biases as comparison of sequential vaccinations. As long as biases are the same for boys and girls, and are proportional to the mortality level, they would not affect the estimated MRR for girls compared with boys. The more likely methodological problem in analyses of the female-male MRR of DTP vaccinated children is that the children could have received the subsequent MV during follow-up. If that were the case, it would lead to a conservative estimate because MV is associated with lower female mortality (11) and would dilute the effect of DTP. To prevent such misclassification, we have tried to restrict follow-up to age groups (less than 9 months) or situations (hospital admissions, war) in which it is unlikely that MV would have been provided during follow-up -in these situations we can be fairly sure that DTP has remained the "most recent vaccination".