1 Projecto de Saude de Bandim, Bissau, Guinea-Bissau, and Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark.
2 Centre for International Health, University of Bergen, Norway.
3 Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Frederiksberg, Denmark
Christine Stabell Benn, Danish Epidemiology Science Centre, Statens Serum Institut, DK-2300 Copenhagen S, Denmark. E-mail: cb{at}ssi.dk.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Accepted 23 April 2003
Vitamin A supplementation to children above 6 months of age reduces all-cause mortality by 23%1 to 30%2,3 in low-income countries. The beneficial effect of vitamin A supplementation is assumed to be due to the prevention of vitamin A deficiency.1 The World Health Organization (WHO) therefore recommends administration of vitamin A at vaccination contacts in order to prevent vitamin A deficiency.4 Until recently, the policy has been to supplement 100 000 IU of vitamin A at the earliest possible opportunity after 6 months of age. However, it has recently been recommended that an additional 50 000 IU of vitamin A be administered with each of the diphtheria-tetanus-pertussis (DTP)/polio vaccinations, which are usually given at 6, 10, and 14 weeks of age.5
![]() |
Contradictions in current knowledge |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Age pattern
Though studies on vitamin A supplementation after 6 months of age consistently have revealed a beneficial effect on child survival, the studies in infants younger than 6 months of age have reported inconsistent effects (Table 1). The two studies of vitamin A supplementation at birth suggest significant reductions in infant mortality (Table 1
).6,7 However, all recent studies of vitamin A given between 1 and 5 months of age failed to demonstrate the expected reduction in all-cause mortality (Table 1
). A meta-analysis of the two studies providing vitamin A at birth (Table 1
) and the four studies providing vitamin A between 1 and 5 months of age (Table 1
), and the studies providing vitamin A from 6 months of age (using the estimate obtained in Beatons meta-analysis1) showed that the effect of vitamin A supplementation between 1 and 5 months of age differed significantly from the effect at birth (P for homogeneity of effects = 0.02) and the effect from 6 months of age (P for homogeneity = 0.009). The lack of beneficial effect between 1 and 5 months of age has been ascribed to breastfeeding covering the needs, whereas older children become increasingly deficient and therefore benefit more from vitamin A supplementation.8 However, several studies indicate that many of the young infants were vitamin A deficient,9,10 and the explanation would not account for the beneficial effect at birth.
|
Increased mortality with increasing nutritional status
In one Nepalese study of children aged 16 months, vitamin A compared with placebo was associated with increasing mortality with increasing mid-upper-arm-circumference (MUAC); the MR for vitamin A supplementation being 1.01 (95% CI: 0.73, 1.42) for children with a MUAC of <105 mm, 1.40 (95% CI: 0.78, 2.50) for a MUAC at 105124 mm, and 1.95 (95% CI: 0.88, 4.32) for a MUAC 125 mm (age-adjusted test for trend, P = 0.07, Table 1
). The result was characterized as perplexing and no explanation was put forward.8 Furthermore, the results are in contrast with the Indonesian study of newborns; MR decreased with increasing birthweight when supplementation was given at birth but increased with another measure of malnutrition (MUAC) when vitamin A supplementation was given between 1 and 6 months of age. None of the other studies that supplemented at birth or between 1 and 5 months of age have reported data on any interaction with nutritional status.
No association with degree of pre-existing deficiency
Even though the presence of xerophthalmia is a useful indicator of severe vitamin A deficiency, a meta-analysis reported that there was no association between the prevalence of xerophthalmia in a population and the effect of vitamin A supplementation in the population.1
No association between dose and effect
There is no clear evidence that a large dose is better than a small dose,1 the tendency being rather the opposite: in a WHO multicentre placebo-controlled study of vitamin A supplementation with routine immunizations in infancy,9 the children in the vitamin A group received 25 000 IU of vitamin A with each of the first three DTP/poliomyelitis vaccines at 6, 10, and 14 weeks of age. At the age of 9 months, with measles vaccination, infants in the vitamin A group were given a further dose of 25 000 IU, and those in the control group received 100 000 IU vitamin A. There was no difference in mortality after the first three doses of vitamin A between the two groups, and there was no difference in any measure of vitamin A status at 9 months of age,12 when the infants received measles vaccine and additional vitamin A supplementation (Table 2). However, we analysed the data from 9 to 12 months of age and found that the control children receiving 100 000 IU vitamin A with measles vaccine at 9 months of age had substantially higher mortality (MR = 2.36 [95% CI: 1.17, 4.77]) than the previously supplemented group, who only received 25 000 IU of vitamin A together with measles vaccine at 9 months of age (Table 2
). The observation was dismissed as being unplanned and not consistent with other studies of the effect of vitamin A supplementation after 6 months of age.
|
![]() |
Hypothesis |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We hypothesize that the mortality effect of vitamin A supplementation 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.
![]() |
Possible biological mechanisms |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Vitamin A acts as an adjuvant to vaccines, and vitamin A supplementation has, under different circumstances, been shown to enhance both cellular and humoral immune responses in animals as well as in humans.32,33 It was recently reported that in mice, the effect of vitamin A supplementation depends on the environment under which it is given; when vitamin A supplementation was given with cytokines that promote Th1 development, enhancement of the Th1 response was observed; when vitamin A was given with cytokines that promote Th2 development, enhancement of the Th2 response was observed.34 Vitamin A seemed to act directly on the APC.34 Hence, vitamin A may be a rather uncritical enhancer of ongoing processes in the immune system at the moment of supplementation. We find it biologically plausible that vitamin A supplementation may amplify ongoing immune reactions induced by vaccinations; when given with a live vaccine it may thus further enhance the capacity of the APC for Th1-polarizing signals, whereas when given with a killed vaccine it may further enhance the capacity of the APCs for Th2-polarizing signals. A synergistic stimulatory effect on the immune system of simultaneous administration of BCG and vitamin A is well known from experimental cancer treatment.3537
![]() |
Resolutions |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Age pattern
The hypothesis would explain the beneficial effect of vitamin A supplementation when given at the time of BCG vaccination at birth and at the time of measles vaccination after 6 months of age. It would also explain the apparent lack of effect or even slightly negative effect when given in the time window of DTP vaccinations between 1 and 5 months of age in spite of pre-existing vitamin A deficiency.
No effect in low birthweight (LBW) neonates
In the Indonesian study, BCG vaccination was postponed in LBW or premature infants until they reached the gestational age of 9 months (personal communication, Dr Cissy B Kartasasmita, Department of Child Health, HSGH). LBW infants were therefore less likely to have received BCG and vitamin A at the same time, and this may explain why vitamin A given at birth had limited effect in these infants.
Increased mortality with increasing nutritional status
If vitamin A supplementation amplifies a possible negative mortality effect of the DPT vaccine, this could become more evident in infants with high MUAC and thus presumably better nutritional status, because they would not benefit in other ways from the extra vitamin A.
No association with degree of pre-existing deficiency
If the effect of vitamin A supplementation were partly due to amplification of the non-specific effects of vaccines, the effect of vitamin A supplementation would be expected to depend on the vaccines with which it is given and not just pre-existing deficiency.
No association between dose and effect
Compared to placebo, 100 000 IU given after 6 months of age reduces mortality. However, the effect of giving 25 000 versus 100 000 IU with measles vaccine has not been investigated elsewhere. It is possible that a small dose of 25 000 IU is even better than a large dose of 100 000 IU for producing a balanced and beneficial immune response to the measles vaccine.
![]() |
Addressing the hypothesis |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Three hundred infants were randomly allocated to receive standard Schwarz measles vaccine (MV) or inactivated polio vaccine (IPV) at 6 months of age. Within each of the two vaccination groups, the infants were allocated randomly to receive 100 000 IU of vitamin A or placebo. At 9 months of age, all infants received MV and the same vitamin A supplement or placebo as given previously (Figure). A third group of infants (those being too old to be enrolled for the 6-month vaccination in the beginning of the study period, and those coming too late during the study period) received MV at 9 months of age. These infants were allocated randomly to 100 000 IU vitamin A or placebo given with the MV. There were no differences in mortality-related parameters between vitamin A and placebo recipients within each of the vaccination groups at baseline. The children were followed intensively to 18 months of age. By this age, the 227 (78 + 70 + 79) children, who had received vitamin A and MV (one or two doses) had a mortality ratio (MR) of 0.46 (95% CI: 0.14, 1.47) compared with the 235 (72 + 68 + 95) children, who had received placebo and MV (Figure).
|
![]() |
Conclusion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The proposed hypothesis accounts for all of these observations but should obviously be tested in future studies.
We have focused on the effect of vitamin A supplementation on mortality. However, the area of vitamin A supplementation and morbidity is also burdened by inconsistent observations. For instance, vitamin A used as therapy for measles and diarrhoea seems beneficial, whereas there seems to be no effect, or even a tendency for negative effects when vitamin A is given during respiratory diseases.1,41 It has been suggested that the effects of vitamin A supplementation used as therapy during infectious diseases are disease-specific because vitamin A acts not only by repleting tissue vitamin A, but also as an adjuvant.42 This suggestion is in line with our hypothesis; if vitamin A amplifies ongoing immune reactions, it is conceivable that this might in some instances be beneficial, in other instances harmful, depending on the type of immune response that the disease elicits.
![]() |
Relevance |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
KEY MESSAGES
|
![]() |
Acknowledgments |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Fawzi WW, Chalmers TC, Herrera MG, Mosteller F. Vitamin A supplementation and child mortality. A meta-analysis. JAMA 1993; 269:898903.[Abstract]
3 Glasziou PP, Mackerras DE. Vitamin A supplementation in infectious diseases: a meta-analysis. BMJ 1993;306:36670.[ISI][Medline]
4 Vitamin A Supplements. A Guide to their Use in the Treatment and Prevention of Vitamin A Deficiency and Xerophthalmia. Prepared by a WHO/ UNICEF/IVACG Task Force. Geneva: World Health Organization, 1997.
5 Sommer A, Davidson FR. Assessment and control of vitamin A deficiency: the Annecy Accords. J Nutr 2002;132:2845S50S.
6 Humphrey JH, Agoestina T, Wu L et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996;128:48996.[ISI][Medline]
7 Rahmathullah L, Tielsh JM, Thulasiraj RD et al. Impact of vitamin A supplementation to newborns on early infant mortality: a community-based randomized trial in South India. BMJ (in press).
8 West KP Jr, Katz J, Shrestha SR et al. Mortality of infants <6 months of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am J Clin Nutr 1995;62:14348.[Abstract]
9 Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy. WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group. Lancet 1998;352:125763.[CrossRef][ISI][Medline]
10 Rahman MM, Mahalanabis D, Wahed MA, Islam MA, Habte D. Administration of 25 000 IU vitamin A doses at routine immunisation in young infants. Eur J Clin Nutr 1995;49:43945.[ISI][Medline]
11 Tolba AM, Hewedy FM, al Senaidy AM, al Othman AA. Neonates vitamin A status in relation to birth weight, gestational age, and sex. J Trop Pediatr 1998;44:17477.[Abstract]
12 Bahl R, Bhandari N, Wahed MA, Kumar GT, Bhan MK. Vitamin A supplementation of women postpartum and of their infants at immunization alters breast milk retinol and infant vitamin A status. J Nutr 2002;132:324348.
13 Semba RD, Munasir Z, Akib A et al. Integration of vitamin A supplementation with the Expanded Programme on Immunization: lack of impact on morbidity or infant growth. Acta Paediatr 2001;90:110711.[CrossRef][ISI][Medline]
14 Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea- Bissau, West Africa. BMJ 2000; 321:143538.
15 Velema JP, Alihonou EM, Gandaho T, Hounye FH. Childhood mortality among users and non-users of primary health care in a rural west African community. Int J Epidemiol 1991;20:47479.[Abstract]
16 Garly ML, Martins CL, Bale C et al. BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa: A non-specific beneficial effect of BCG? Vaccine 2003;21:278290.[CrossRef][ISI][Medline]
17 Desgrees du LA, Pison G, Aaby P. Role of immunizations in the recent decline in childhood mortality and the changes in the female/male mortality ratio in rural Senegal. Am J Epidemiol 1995;142:64352.[Abstract]
18 Aaby P, Bhuyia A, Nahar L et al. The survival benefit of measles immunization may not be explained entirely by the prevention of measles disease: a community study from rural Bangladesh. Int J Epidemiol 2003;32:10615.[CrossRef][ISI][Medline]
19 Aaby P, Samb B, Simondon F, Seck AM, Knudsen K, Whittle H. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. BMJ 1995;311:48185.
20 Shann F. Non-specific effects of vaccines in developing countries. We need evidence about the effect of vaccines on mortality from all causes. BMJ 2000;321:142324.
21 Aaby P, Jensen H, Garly ML, Bale C, Martins C, Lisse I. Routine vaccinations and child survival in a war situation with high mortality: effect of gender. Vaccine 2002;21:1520.[CrossRef][ISI][Medline]
22 Aaby P, Jensen H, Samb B et al. Differences in female-male mortality after high-titre measles vaccine may have been associated with subsequent vaccination with DTP and IPV: A re-analysis of the West African studies. Lancet 2003;361:218388.[CrossRef][ISI][Medline]
23 Global Advisory Committee on Vaccine Safety. Potential adverse effects of routine vaccinations on child survival. Weekly Epidemiol Rec 2002;77:39394.
24 Upham JW, Lee PT, Holt BJ et al. Development of interleukin-12-producing capacity throughout childhood. Infect Immun 2002;70: 658388.
25 Marchant A, Goetghebuer T, Ota MO et al. Newborns develop a Th1-type immune response to Mycobacterium bovis bacillus Calmette-Guerin vaccination. J Immunol 1999;163:224955.
26 Pabst HF, Spady DW, Carson MM, Stelfox HT, Beeler JA, Krezolek MP. Kinetics of immunologic responses after primary MMR vaccination. Vaccine 1997;15:1014.[CrossRef][ISI][Medline]
27 Graham BS, Henderson GS, Tang YW, Lu X, Neuzil KM, Colley DG. Priming immunization determines T helper cytokine mRNA expression patterns in lungs of mice challenged with respiratory syncytial virus. J Immunol 1993;151:203240.
28 Waris ME, Tsou C, Erdman DD, Zaki SR, Anderson LJ. Respiratory syncitial virus infection in BALB/c mice previously immunized with formalin-inactivated virus induces enhanced pulmonary inflammatory response with a predominant Th2-like cytokine pattern. J Virol 1996; 70:285260.[Abstract]
29 Moran TM, Park H, Fernandez-Sesma A, Schulman JL. Th2 responses to inactivated influenza virus can Be converted to Th1 responses and facilitate recovery from heterosubtypic virus infection. J Infect Dis 1999;180:57985.[CrossRef][ISI][Medline]
30 Fischer JE, Johnson TR, Peebles RS, Graham BS. Vaccination with pertussis toxin alters the antibody response to simultaneous respiratory syncytial virus challenge. J Infect Dis 1999;180:71419.[CrossRef][ISI][Medline]
31 Rowe J, Macaubas C, Monger TM et al. Antigen-specific responses to diphtheria-tetanus-acellular pertussis vaccine in human infants are initially Th2 polarized. Infect Immun 2000;68:387377.
32 Ross AC. Vitamin A status: relationship to immunity and the antibody response. Proc Soc Exp Biol Med 1992;200:30320.[Medline]
33 Stephensen CB. Vitamin A, infection, and immune function. Annu Rev Nutr 2001;21:16792.[CrossRef][ISI][Medline]
34 Hoag KA, Nashold FE, Goverman J, Hayes CE. Retinoic acid enhances the T helper 2 cell development that is essential for robust antibody responses through its action on antigen-presenting cells. J Nutr 2002;132:373639.
35 Pang AS, Morales A. Chemoimmunoprophylaxis of an experimental bladder cancer with retinoids and Bacillus Calmette Guerin. J Urol 1983;130:16670.[ISI][Medline]
36 Kurata T, Micksche M. Suppressed tumor growth and metastasis by vitamin A + BCG in Lewis lung tumor bearing mice. Oncology 1977; 34:21215.[ISI][Medline]
37 Meltzer MS, Cohen BE. Tumor suppression by Mycobacterium bovis (strain BCG) enhanced by vitamin A. J Natl Cancer Inst 1974; 53:58587.[ISI][Medline]
38 Benn CS, Aaby P, Bale C et al. Randomised trial of effect of vitamin A supplementation on antibody response to measles vaccine in Guinea-Bissau, west Africa. Lancet 1997;350:10105.[CrossRef][ISI][Medline]
39 Benn CS, Balde A, George E et al. Effect of vitamin A supplementation on measles-specific antibody levels in Guinea-Bissau. Lancet 2002; 359:131314.[CrossRef][ISI][Medline]
40 Cytel Software Corporation, Cambridge. LogXact for Windows. Logistic regression software featuring exact methods 2000.
41 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]
42 Ross AC. Vitamin A supplementation as therapyare the benefits disease specific? Am J Clin Nutr 1998;68:89.
43 Daulaire NM, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR. Childhood mortality after a high dose of vitamin A in a high risk population. BMJ 1992;304:20710.[ISI][Medline]
44 Humphrey JH. Impact of Vitamin A Supplementation of Mothers and Babies on Infant Mortality, HIV MTCT and New Maternal HIV Infections. XXI IVACG Meeting, Morocco 2003.