In this randomized trial we observed that combined supplementation with vitamin A and zinc reduced the burden of clinical attacks of malaria in young children by 30%. These results suggest that vitamin A and zinc supplementation might play an important role in the prevention of malaria. Vitamin A alone previously has been demonstrated to lead to a reduction of malaria episodes by 30% in Papua New Guinea . Similarly, it was also observed that zinc supplementation alone reduced P. falciparum-attributable health attendance by 38% and by 69% for malaria episodes with high parasite density ≥ 100 000/μl . When considering these previous studies [10, 11], our results are suggestive of a potential synergistic effect of vitamin A and zinc on the reduction malaria episodes, even with low levels of parasitemia. However, because there were no groups of participants who received vitamin A or zinc alone in the present study, the study design precludes determining whether the reduction in malaria episodes was additive or multiplicative (i.e., synergistic). Mean parasite density observed during the follow up period tended to occur at higher densities in the placebo group. Prolongation of the time to first malaria episode manifestation was observed in one zinc supplementation study  but not in a vitamin A supplementation trial , so this lends support to a zinc-specific effect. Zinc appears to have an effect beyond an impact on malaria alone as many studies have shown that zinc reduces morbidity due to numerous infectious diseases [19–22]. Vitamin A seems to have a positive impact in terms of the number of malaria cases, independently from the P. falciparum parasitemia . However, in previous studies in Ghana and in Burkina Faso, no effect was found on the number of falciparum malaria episodes or on mean parasite density with the supplementation of zinc alone or vitamin A alone [13, 14].
One important limitation of our study was the imbalance at randomization between the two study arms. For example, the supplemented group had more children who were parasitemic at baseline, more who had a history of fever, and a greater proportion who were anemic. While the radical cure with SP should have resulted in the elimination of these differences between the two groups, it is possible that a greater intensity of past exposure to malaria in the intervention group might have resulted in a greater degree of acquired immunity which in turn could have led to a slower rate of re-infection. However, another possibility is that the study results are underestimating the true effect of the combined vitamin A and zinc supplements because the intervention group might have been subjected to a greater intensity of malaria transmission.
We observed that the number of fever episodes was significantly lower in children who received the supplements. In Papua New Guinea there was no effect of vitamin A alone on the number of fever episodes . This confirms that the mechanism of action on malaria morbidity of vitamin A or zinc remains complex. It has been demonstrated that free retinol has a pharmacological effect against malaria parasites , but the very low concentrations of free retinol in the serum make its hypothetical effect inconclusive  given the lack of association between serum retinol concentration and malaria morbidity found in Papua New Guinea . In another zinc supplementation study in Papua New Guinea , it was observed that plasma zinc levels alone were not predictive of susceptibility to malaria episodes, and despite the moderate improvement of plasma zinc levels in the supplemented group, malaria-associated morbidity was strongly reduced. These findings suggest that daily intake of zinc could modify resistance to P. falciparum episodes though pathways, perhaps at the cellular level, that are not fully reflected in plasma zinc levels .
It is known that vitamin A has immunopotentiating activities ; zinc also is essential for normal immune function . Consequently, dual supplementation of these two micronutrients may lead to enhanced acquisition of immunity against falciparum malaria or to modified resistance to malaria episodes through a pathway at the cellular level . These ideas are supported by the fact that the mean number of fever and malaria episodes was significantly lower in the supplemented group. Supplementation with vitamin A as well as zinc, or a combination of the two, is recognised to have a positive impact on anaemia [26–29], as observed in the current study. Improvements in anaemia might have resulted in reduced risk of fever and malaria rather than an immunododulating effect of the two micronutrients. Children in the supplemented group were more likely to be free from any pathological episode. Vitamin A supplementation provided simultaneously with expanded program on immunization (EPI) campaigns adopted by most of African in accordance with the recommendations of UNICEF represents a useful strategic approach to address the problem of vitamin A deficiency. However current strategies have not taken zinc supplementation into consideration with the notable exception of diarrhoea treatment programs. Ours findings suggest that dual supplementation with vitamin A and zinc is effective against malaria, and that a longer supplementation period might lead us to observe more important beneficial effects. Ultimately, the more affordable and sustainable solution would be the incorporation of vitamin A and zinc in food fortification for children.