Final Report Summary - CHILIC (Child health intervention interactions in low-income countries)
In the present project the PI and her team conducted a series of inter-disciplinary epidemiological and immunological studies of the two most widely used health interventions in global health: vitamin A and vaccines.
The overriding hypothesis is that vitamin A and vaccines – beside the obvious specific effects on vitamin A deficiency and on the target diseases – also have non-specific effects on the immune system and can modulate the response to other infections. These effects can be different for boys and girls, and they are not trivial, but can significantly affect these children’s chance of survival. Furthermore, the interventions interact, so the combination and sequence in which they are given is very important.
The PI and her team conducted four randomized controlled trials (RCT, one is still ongoing) and three nested immunological subgroup studies in Guinea-Bissau. The results are briefly summarized below.
In the first RCT, the WHO policy of providing high-dose vitamin A supplementation (VAS) with vaccines was tested. The policy is believed to reduce overall mortality by 24%. We found no such effect. VAS had strong sex-differential effects, it almost halved mortality in females, but in contrast, there was a tendency for increased mortality in males.
The results have fuelled a heated and still ongoing debate on the value of continuing the VAS policy, substituting it with smaller more frequent doses, or improving nutrition in general. Based on the existing and new evidence, the PI has argued that VAS is an immune-modulator, and may be very beneficial in some situations, but harmful in others - depending on the sex of the child, and what is going on in the immune system. Hence, it may be that VAS is beneficial even if a child is not vitamin A deficient, and in contrast it may be that a child should not receive VAS even if deficient. To optimize the vitamin A policy, and importantly to avoid harming some children, the PI proposes that we need to conduct large-scale RCTs aimed to test in three arms the benefits of high-doses versus lower frequent doses versus placebo.
In the second RCT, the effect of providing BCG at birth to low birth weight children was tested. In this first RCT with neonatal mortality as an outcome, we confirmed previous findings from two other RCTs: BCG at birth to low birth weight neonates is associated with significant reductions in neonatal mortality. The effects are seen very early after administration. WHO recently acknowledged, that “The available data suggest that the current WHO recommended schedule for BCG vaccine has a beneficial effect on all-cause mortality and this should be emphasized”
In the third RCT, we tested for the first time ever the current WHO policy of providing oral polio vaccine (OPV) at birth. We found that this policy is associated with a 32% reduction in infant mortality. This result has potentially very large consequences for the current WHO initiative to eradicate polio and switch from OPV to inactivated polio vaccine. The results have just been communicated to the WHO.
In the immunological studies we showed that vitamin A and BCG indeed have non-specific immunological effects, which differed between the sexes. The effects of OPV were more subtle, but perhaps the blood was not the right place to look, since OPV is given orally and evokes its greatest response in the gut. Nonetheless we were able to confirm that when given with BCG, OPV reduces the specific immune response to BCG, a direct interaction between the two vaccines.
Thus, we were able to confirm the hypothesis that vitamin A and vaccines have important non-specific effects on the immune system. These effects can be different for boys and girls, and they are not trivial, but can significantly affect these children’s chance of survival. Furthermore, the interventions interact, so the combination and sequence in which they are given is very important.
The overriding hypothesis is that vitamin A and vaccines – beside the obvious specific effects on vitamin A deficiency and on the target diseases – also have non-specific effects on the immune system and can modulate the response to other infections. These effects can be different for boys and girls, and they are not trivial, but can significantly affect these children’s chance of survival. Furthermore, the interventions interact, so the combination and sequence in which they are given is very important.
The PI and her team conducted four randomized controlled trials (RCT, one is still ongoing) and three nested immunological subgroup studies in Guinea-Bissau. The results are briefly summarized below.
In the first RCT, the WHO policy of providing high-dose vitamin A supplementation (VAS) with vaccines was tested. The policy is believed to reduce overall mortality by 24%. We found no such effect. VAS had strong sex-differential effects, it almost halved mortality in females, but in contrast, there was a tendency for increased mortality in males.
The results have fuelled a heated and still ongoing debate on the value of continuing the VAS policy, substituting it with smaller more frequent doses, or improving nutrition in general. Based on the existing and new evidence, the PI has argued that VAS is an immune-modulator, and may be very beneficial in some situations, but harmful in others - depending on the sex of the child, and what is going on in the immune system. Hence, it may be that VAS is beneficial even if a child is not vitamin A deficient, and in contrast it may be that a child should not receive VAS even if deficient. To optimize the vitamin A policy, and importantly to avoid harming some children, the PI proposes that we need to conduct large-scale RCTs aimed to test in three arms the benefits of high-doses versus lower frequent doses versus placebo.
In the second RCT, the effect of providing BCG at birth to low birth weight children was tested. In this first RCT with neonatal mortality as an outcome, we confirmed previous findings from two other RCTs: BCG at birth to low birth weight neonates is associated with significant reductions in neonatal mortality. The effects are seen very early after administration. WHO recently acknowledged, that “The available data suggest that the current WHO recommended schedule for BCG vaccine has a beneficial effect on all-cause mortality and this should be emphasized”
In the third RCT, we tested for the first time ever the current WHO policy of providing oral polio vaccine (OPV) at birth. We found that this policy is associated with a 32% reduction in infant mortality. This result has potentially very large consequences for the current WHO initiative to eradicate polio and switch from OPV to inactivated polio vaccine. The results have just been communicated to the WHO.
In the immunological studies we showed that vitamin A and BCG indeed have non-specific immunological effects, which differed between the sexes. The effects of OPV were more subtle, but perhaps the blood was not the right place to look, since OPV is given orally and evokes its greatest response in the gut. Nonetheless we were able to confirm that when given with BCG, OPV reduces the specific immune response to BCG, a direct interaction between the two vaccines.
Thus, we were able to confirm the hypothesis that vitamin A and vaccines have important non-specific effects on the immune system. These effects can be different for boys and girls, and they are not trivial, but can significantly affect these children’s chance of survival. Furthermore, the interventions interact, so the combination and sequence in which they are given is very important.