USDA Western Human Nutrition Research Center, and Nutrition Department, University of California, Davis, CA 956168669, USA. E-mail: cstephensen{at}ucdavis.edu
Vitamin A supplements in community intervention trials seem to provide maximum protection against death from infectious diseases when provided at birth or after 6 months of age.1 Why this is so is not clear and part of the reason may be a lack of data in young infants. However, Benn and colleagues2 have other ideas and have proposed a hypothesis to explain this inconsistency. First, a little background information is in order.
The goals of vitamin A supplementation programmes in areas of the world where vitamin A deficiency is a public health problem are, of course, to treat and prevent vitamin A deficiency. The principal adverse consequences of vitamin A deficiency are xerophthalmia and increased risk of death from infectious diseases. Decreasing mortality risk has become the principal goal of vitamin A supplementation programmes in the past decade. Many large-scale community intervention trials have been conducted and a definitive conclusion is that vitamin A supplementation decreases mortality in infants and young children over 6 months of age. Fewer studies have been done in younger infants but the data support a similar benefit, at least if the supplements are given at birth. Speculation on the reason for a lesser effect when supplements are given between birth and 6 months have focused on differences in environmental influences on this age group (e.g. the protection of breastfeeding against malnutrition and infection) or on differences among the populations studied (e.g. different prevalence rates of infectious diseases among study sites may affect underlying mortality rates).3
Although the principal benefits of vitamin A supplementation are well-established, the mechanisms underlying the decreased mortality risk are not understood in great detail. It is known that vitamin A deficiency impairs many aspects of both innate and adaptive immunity and it is presumed that preventing deficiency improves protection against development of severe disease, since total morbidity is little affected by supplements. However, the question of which improvements (e.g. improved mucosal integrity, enhanced T-cell mediated immunity) are causing the decreased mortality has not been answered. Some may argue that understanding how a thing happens is not important in a public health context as long as the desired result of decreased mortality is achieved. However, it is now quite clear that vitamin A improves recovery from some infections (e.g. some diarrhoeal diseases and measles) but not others (e.g. non-measles pneumonia).3 Better understanding of the mechanism of action of vitamin A on immune function would presumably explain these observations and better allow public health practitioners to target their interventions to maximize benefit and minimize risk.
Benn and colleagues2 propose that the effect of vitamin A supplementation on reducing mortality may depend not only on the prevention of vitamin A deficiency, but also on vitamin A amplifying the non-specific immune modulation induced by routine vaccinations. This same research group,4 as well as others more recently,5 have proposed that BCG and measles vaccines provide protection against death from infections other than tuberculosis and measles. They further propose that diphtheria, pertussis, tetanus (DPT) vaccine does not provide such protection. While (again) the underlying mechanism is not clear, the basic idea is that live vaccines may activate the innate immune system in such a way as to provide protection against a variety of pathogens in a way that killed vaccines with alum adjuvants do not. Increased activation of antigen-presenting cells, increased production of type I interferons by a variety of cells, or increased production of T-cell cytokines in lymph node microenvironments are all mechanisms by which such cross-protection might occur.
How does this relate to vitamin A supplementation? Benn and colleagues2 observe that BCG and measles are given at birth and after 6 months, respectively, the times at which vitamin A supplementation provide maximum protection against death. They suggest that vitamin A is acting on the immune system to enhance this effect. Since the vaccines given in intervening months do not provide such non-specific protection, the authors argue, vitamin A has a lesser protective effect. To make their argument Benn and colleagues rely on re-analysis of data from previous studies. Thus they are making unplanned observations. While the queue at the microphone warning of the hazards of such an approach would be long indeed if this manuscript were an oral presentation, it is reasonable to make such comparisons as long as the goal is to generate hypotheses rather than draw firm conclusions. True to this view, the authors give us a hypothesis, and not conclusions.
A significant practical problem with their hypothesis is that neither phenomenon involved in the proposed interactionvitamin A protecting against death from infectious diseases or the cross-protection possibly provided by BCG and measles vaccinesis understood very well at a mechanistic level. In addition, many of the known effects of vitamin A and its derivative retinoic acid would seem to dampen rather than enhance the T-helper type 1 (Th1)-mediated responses that would be expected to accompany BCG and measles immunization.6 Thus at the end of the article this reader (who would have been in the microphone queue at the oral presentation) was left with many more questions than answers. Unfortunately, this situation is not uncommon in the world of nutritional immunology where observations are abundant and mechanisms have been slow to follow.
Is it sufficient for Benn and colleagues to propose a hypothesis based on debatable interpretation of unplanned observations? This reader would say yes because the widespread use of vitamin A and other nutritional supplements in the public health arena to decrease mortality and improve health makes it important to understand the mechanisms underlying the proposed benefits. Nutrients, particularly when given at high doses, may be potent modulators of immune function. Thus their use not only to treat or prevent deficiency, but as therapeutic interventions in infectious and chronic inflammatory diseases, demands better understanding of the underlying mechanisms. Benn and colleagues2 have taken the step of proposing a hypothesis with regard to vitamin A. The hypothesis is incomplete in that a specific mechanism is lacking but it has merit in that it might help explain some current inconsistencies in the literature by providing the basis for further work by this group or by others to help define how vitamin A decreases mortality from infectious diseases.
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2 Benn CS, Balé C, Sommerfelt H, Friis H, Aaby P. Hypothesis: Vitamin A supplementation and childhood mortality: amplification of the non-specific effects of vaccines? Int J Epidemiol 2003:32:82228.
3 Villamor E, Fawzi WW. Vitamin A supplementation: implications for morbidity and mortality in children. J Infect Dis 2000;182(Suppl.1):S12233.[CrossRef][ISI][Medline]
4 Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000; 21:143538.[CrossRef]
5 Kabir Z, Long J, Reddaiah VP, Kevany J, Kapoor SK. Non-specific effect of measles vaccination on overall child mortality in an area of rural India with high vaccination coverage: a population-based case-control study. Bull World Health Organ 2003;81:24450.[ISI][Medline]
6 Stephensen CB. Vitamin A, infection, and immune function. Annu Rev Nutr 2001;21:16792.[CrossRef][ISI][Medline]