As VAS is an important immunomodulator, several groups have studied whether simultaneous administration of VAS influences the immune response to specific vaccines. Apart from one study, no evidence was found for a negative effect of VAS on the immune response to OPV and MV,16
and VAS may even be associated with increased antibody responses to Hepatitis B vaccine12
and to MV, particularly in boys.17
No study, however, has addressed the effect on mortality of VAS given with vaccines. In the present study, VAS with DTP was associated with increased mortality when compared with VAS alone. This contrasted with the effect of VAS with MV, which if anything was associated with decreased mortality.
The present study was observational. Participation was voluntary and depended on the mother bringing the child to a vaccination post, all children received VAS unless they were in a VAS-at-birth trial and eligible children were not randomized to a vaccine. There are considerable differences between the baseline characteristics of the different groups, especially the small group of children missing both DTP and MV seemed to be different. We have attempted to control for known potential confounders, and it should be noted that age is inherently controlled for in the Cox models we used. Nonetheless, there could be considerable residual confounding, and all comparisons between participants and non-participants and between vaccine recipients and non-vaccine-recipients should be judged with caution. However, there are several observations in the present study, which suggest that our findings are not merely the result of confounding.
First, it could be speculated that those who received vaccines during the campaign had more non-compliant mothers (who had not followed the normal vaccination schedule) and therefore a higher risk of dying. In spite of control for maternal schooling and nutritional status, this could have confounded our comparison of VAS with any DTP vs VAS alone. However, this would not explain the contrasting effects of VAS given with any DTP vs VAS given with MV. Though the group missing DTP as well as MV may have been even less compliant than the group missing MV alone, we would not expect it to fully explain the contrasting effects of VAS given with DTP + MV vs VAS given with MV. Furthermore, if a different a priori risk of dying in the different treatment groups explained their different mortality, the mortality ratios should be reduced importantly by control for nutritional status. Since this did not happen, the increased mortality in the VAS with any DTP group does not merely seem to be due to confounding, but may be related to treatment.
Second, we know from previous studies that travelling or ill children are more likely to die,18
and in the present study, the non-participants who were travelling or too ill to participate in the campaign had high mortality. However, non-participants did not have the expected higher mortality compared with participants who received VAS with any DTP. On the contrary, participants who received VAS with any DTP had considerably higher mortality than non-participants. This was not the case for participants who had received VAS with MV. It could be argued that it was only mothers who perceived their children in need of treatment who participated in the NIDs. We did not register illness among participants, but mothers in Guinea-Bissau would normally not bring ill children for vaccinations, as also reflected by the fact that illness in the child was given as a reason for non-participation. Furthermore, a higher proportion of frail children among those coming for VAS and vaccination would not explain why it was only children receiving VAS with DTP who did not benefit from the campaign.
As DTP is associated with increased mortality in girls, and MV is associated with decreased mortality, particularly in girls,19–22
we would a priori expect to find decreased mortality after MV compared with DTP. However, in the present study, the difference in mortality between MV and DTP recipients was far larger than usually observed. Furthermore, among the children who did not receive VAS because they were in a VAS-at-birth trial, the MR (55/1000 pyrs) after DTP alone was lower than the MR among children who received VAS with DTP [140/1000 pyrs ()], suggesting that VAS + DTP may be associated with higher mortality than DTP alone.
Hence, in the present study, we found several indications that VAS given with DTP had negative effects in contrast to VAS given with MV alone. However, we cannot exclude residual confounding in the comparisons of participants and non-participants and between recipients of different vaccines. Furthermore, the number of deaths was small, and it could be argued that it was a chance finding. Based on this study alone, no conclusions regarding the potential interactions between VAS and vaccines can be made. However, it should be noted that all currently available data indicate that the combination of VAS and DTP may be problematic, and we had a priori formulated the hypothesis of a negative effect.4
The WHO recommends VAS at vaccination contacts after the age of 6 months. The first vaccine to be received after 6 months of age would normally be MV. However, many children come late for vaccinations. In Guinea-Bissau, approximately one-third of all children in the urban area and two-thirds in the rural receive at least one DTP vaccine after 6 months of age. Thus, in practice, there will be children coming for MV, DTP or DTP plus MV for their first vaccination contact after 6 months of age. Based on the present evidence, the WHO VAS policy may not be beneficial for children whose first vaccination after 6 months is a DTP vaccine. Large, randomized studies of the impact on survival of the current WHO recommendation of providing VAS at all vaccination contacts after 6 months of age seem warranted.