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

Abstract

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.

Article summary

Article focus

• MV has sex-differential non-specific effects for child survival. We examined whether DTP vaccine has negative effects for survival, particularly for girls.

• We tested six hypotheses suggesting that DTP may have negative health consequences if found to be true.

• Furthermore, we conducted two randomised trials reducing the time of exposure to DTP as most recent vaccination by providing a live vaccine shortly after DTP.

Key messages

• All available studies suggest that the effect of DTP on child survival is opposite of the effects of BCG and MV. In the two natural experiments, DTP-vaccinated children had significantly higher mortality than DTP-unvaccinated children.

• Among DTP-vaccinated children, girls have higher mortality than boys in all studies, whereas the tendency is the opposite for BCG- and measles-vaccinated children. DTP administered after MV in randomised trials of MV is associated with increased female but not male mortality.

• Reducing time of exposure to DTP as the most recent vaccination with BCG or MV reduce child mortality.

Strengths and limitations of this study

• Since the healthiest children are vaccinated first, one would expect DTP to be associated with a benefit. However, all the data suggest consistently that DTP is associated with a negative effect for girls.

• A randomised trial of the effect of DTP on overall survival could not be conducted. There is a need to conduct such studies now.