DTP vaccinations were associated with increased infant mortality even though there was no vaccine-induced herd immunity. When unvaccinated controls were normal children who had not yet been eligible for vaccination, mortality was 5 times higher for DTP-vaccinated children. Co-administration of OPV with DTP may have reduced the negative effects of DTP.

4.2 Strength and Weaknesses

Aaby et al., 2016 Aaby P.

Ravn H.

Benn C.S. The WHO review of the possible non-specific effects of diphtheria-tetanus-pertussis vaccine. The present analysis assessed DTP and child survival in a “natural experiment” in which the children were allocated by the timing of their birth and community weighing sessions and the group allocation was therefore not influenced by the usual selection biases to the same extent as most other studies of DTP (). To assure that the censoring from the main analysis of children who were not vaccinated had not produced the unexpected strong result we made an intention-to-treat analysis but this did not change the result. If anything the unvaccinated children had slightly worse nutritional status before 3 months of age than the children who were subsequently DTP vaccinated (p = 0.09) ( Table 2 ); the unvaccinated children travelled more than the DTP vaccinated children. These biases would tend to favor rather than increase mortality in the DTP group and the estimates from the natural experiment may therefore still be conservative.

The estimated effects of DTP and OPV are unlikely to have been influenced by other vaccinations since very few had received other vaccines; if the children who may have received BCG were censored in the analysis the result was essentially the same (Supplementary Table 2).

The 3-monthly community examinations assured that we had follow-up information for all children and relatively accurate information on the time of death. Some children were excluded because a BHP card could not be found and we did not know whether they had been vaccinated or were travelling. Most likely, BHP cards may never have been made because the child was not coming for examination, or the card may have disappeared at community examinations, at the later handling of BHP cards by field workers or data entry clerks, or due to mice. However, the few missing cards are unlikely to have affected the main analysis as the mortality rate in this group was similar to the general mortality rate ( Fig. 2 ).

To assure comparability of vaccinated and unvaccinated groups, also with respect to travelling, we included only children who had been weighed in Bandim in connection with the 3-monthly community examinations. This meant that children who mostly stayed outside the area were not included in the analysis; these children had no access to community vaccinations and they lived elsewhere where the mortality risk might have been quite different, e.g. due to a higher risk of malaria infection.

The present study was not a planned trial. The study would have been a cleaner natural experiment if vaccinations had only been administered at the weighing sessions. However, the expatriate nurse did organize additional vaccinations and some ‘unvaccinated’ children had therefore already received a vaccination before coming for a weighing session. These ‘misclassifications’ do not explain the increased mortality in the DTP group. The estimate for DTP-vaccinated (± OPV) compared with DTP-unvaccinated children was 4-fold higher mortality when we included these additional landmarks in the analysis.