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

Peter Aaby, Christine Benn, Jens Nielsen, Ida Maria Lisse, Amabelia Rodrigues, Henrik Ravn, Peter Aaby, Christine Benn, Jens Nielsen, Ida Maria Lisse, Amabelia Rodrigues, Henrik Ravn

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.

Conflict of interest statement

Competing interests: None.

Figures

Figure 1
Figure 1
Vaccination schedule in Guinea-Bissau. Note: the vaccination schedule in Guinea-Bissau was changed in 2008. Pentavalent vaccine (DTP + hepatitis B virus + Hib) has replaced DTP, yellow fever is administered with measles vaccine and the booster doses of DTP and OPV have been removed. DTP, diphtheria–tetanus–pertussis; OPV, oral polio vaccine.
Figure 2
Figure 2
Female–male mortality ratios in community studies from the prevaccination era in West Africa (see supplementary table 1).
Figure 3
Figure 3
The research process. DTP, diphtheria–tetanus–pertussis; HTMV, high-titre measles vaccine; MV, measles vaccine.
Figure 4
Figure 4
Mortality ratios for different routine vaccinations within the same study (observation I) (see supplementary table 2). DTP, diphtheria–tetanus–pertussis; MV, measles vaccine.
Figure 5
Figure 5
Female–male (F/M) mortality ratios for diphtheria–tetanus–pertussis (DTP)-vaccinated children in studies of DTP administered after no previous vaccine or after BCG (other studies) and before measles vaccine (observation III) (see supplementary table 3).
Figure 6
Figure 6
Female–male mortality ratios for diphtheria–tetanus–pertussis (DTP)-, BCG- and measles vaccine (MV)-vaccinated children (observation III) (see supplementary table 4).
Figure 7
Figure 7
Mortality or morbidity patterns among diphtheria–tetanus–pertussis (DTP)-vaccinated and measles-vaccinated children of similar age (observation III). One additional study of female–male twins could not be presented graphically because one group had no deaths; this study had significant differential effects of DTP and MV (see supplementary table 5).
Figure 8
Figure 8
Mortality after enrolment in measles vaccination trials according to diphtheria–tetanus–pertussis (DTP) status at enrolment: missing DTP vaccinations versus fully DTP vaccinated (observation V) (see supplementary table 6 with two additional small studies which could not be presented due to undefined estimates).
Figure 9
Figure 9
Mortality rate ratios for measles vaccine age group versus diphtheria–tetanus–pertussis age group (observation VI) (see supplementary table 7).
Figure 10
Figure 10
Age- and sex-specific mortality curves from Gambia and Malawi.

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