Non-specific effects of BCG and DTP vaccination on infant mortality: An analysis of birth cohorts in Ghana and Tanzania.

BACKGROUND: Vaccines may induce non-specific effects on survival and health outcomes, in addition to protection against targeted pathogens or disease. Observational evidence suggests that infant Baccillus Calmette-Guérin (BCG) vaccination may provide non-specific survival benefits, while diphtheria-tetanus-pertussis (DTP) vaccination may increase the risk of mortality. Non-specific vaccine effects have been hypothesized to modify the effect of neonatal vitamin A supplementation (NVAS) on mortality. METHODS: 22,955 newborns in Ghana and 31,999 newborns in Tanzania were enrolled in two parallel, randomized, double-blind, placebo-controlled trials of neonatal vitamin A supplementation from 2010 to 2014 and followed until 1-year of age. Cox proportional hazard models were used to estimate associations of BCG and DTP vaccination with infant survival. RESULTS: BCG vaccination was associated with a decreased risk of infant mortality after controlling for confounders in both countries (Ghana adjusted hazard ratio (aHR): 0.51, 95% CI: 0.38-0.68; Tanzania aHR: 0.08, 95% CI: 0.07-0.10). Receiving a DTP vaccination was associated with a decreased risk of death (Ghana aHR: 0.39, 95% CI: 0.26-0.59; Tanzania aHR: 0.19, 95% CI: 0.16-0.22). There was no evidence of interaction between BCG or DTP vaccination status and infant sex or NVAS. CONCLUSION: We demonstrated that BCG and DTP vaccination were associated with decreased risk of infant mortality in Ghana and Tanzania with no evidence of interaction between DTP or BCG vaccination, NVAS, and infant sex. Our study supports global recommendations on BCG and DTP vaccination and programmatic efforts to ensure all children have access to timely vaccination. CLINICAL TRIALS REGISTRATION: Ghana (Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000582055) and Tanzania (ANZCTR: ACTRN12610000636055).

Vitamin A status and body pool size of infants before and after consuming fortified home-based complementary foods.

BACKGROUND: Home fortification using sachets of micronutrient powder (e.g. "Sprinkles") is a food-based approach offering an alternative to high dose vitamin A (VA) supplements for infants. The primary objective was to investigate the impact of VA-home fortification on infant VA pool size. The secondary objective was to compare VA status of infants assessed by the modified relative dose response (MRDR) test before and the (13)C-retinol isotope dilution ((13)C-RID) test in the same infants after vitamin A supplementation. METHODS: A randomized-controlled trial was conducted in 7-9 month old infants in Ghana. Eligible children were randomly allocated to receive a daily sachet of "Sprinkles" with or without VA for 5 months added to complementary foods. The MRDR test indirectly determined VA liver reserves at baseline and the (13)C-RID determined VA body pool at follow-up in the same cohort of children. RESULTS: At baseline, the MRDR values (95 % CI) for infants were comparable in the intervention and control groups: normal at 0·032 (SD 0·018) (0·025-0·038) and 0·031 (SD 0·018) (0·024-0·038), respectively. After intervention, total body stores (TBS) and liver retinol concentrations did not differ between intervention and control groups; TBS were 436 (SD 303) and 434 (SD 186) µmol, respectively, and estimated liver concentrations were 0·82 (SD 0·53) and 0·79 (SD 0·36) µmol/g liver, indicating adequate reserves in all children. CONCLUSIONS: Both the MRDR and (3)C-RID tests confirmed that the infants had adequate VA status before and after home fortification of their complementary foods. These tests offered more information than serum retinol concentrations alone, which predicted VA deficiency using current suggested cutoffs not corrected for inflammation status.

Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Results of randomised controlled trials of newborn (age 1-3 days) vitamin A supplementation have been inconclusive. The WHO is coordinating three large randomised trials in Ghana, India, and Tanzania (Neovita trials). We present the findings of the Neovita trial in Ghana. METHODS: This study was a population-based, individually randomised, double-blind, placebo-controlled trial in the Brong Ahafo region of Ghana. The trial participants were infants aged at least 2 h, identified at home or facilities on the day of birth or in the next 2 days, able to feed orally, and likely to stay in the study area for at least 6 months. They were randomly assigned (ratio 1:1) to receive either one oral dose of vitamin A (50,000 IU) or placebo immediately after recruitment. The research team and parents of the infants were masked to treatment assignment. Follow-up home visits were undertaken every 4 weeks, when data were recorded for deaths, facility use, and care seeking. The primary outcome was post-supplementation mortality to 6 months of age. Analysis was by intention to treat. Potential adverse events were recorded at 1 and 3 days after supplementation. This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR)CTRN12610000582055. FINDINGS: We assessed 26,414 livebirths for eligibility between Aug 16, 2010, and Nov 7, 2011. We recruited 22,955 newborn infants, with 11,474 randomly assigned to receive vitamin A and 11,481 to receive placebo. Loss to follow-up was low with vital status at 6 months of age reported for 22,698 (98·9%) infants. We recorded 278 post-supplementation deaths to 6 months of age in the vitamin A group (mortality risk 24·5 in 1000 supplemented infants) and 248 deaths in the placebo group (mortality risk 21·8 per 1000 supplemented infants), relative risk (RR) 1·12 (95% CI 0·95-1·33; p=0·183) and risk difference (RD) 2·66 (95% CI -1·25 to 6·57; p=0·18). Adverse events within 3 days of supplementation did not differ by trial group. 122 infants died in the first 3 days after supplementation; 70 (0·6%) in the vitamin A and 52 (0·5%) in the placebo group (risk ratio [RR] 1·35, 95% CI 0·94-1·93, p=0·102). 53 infants were reported to have a bulging fontanelle; 32 (0·3%) in the vitamin A group and 21 (0·2%) in the placebo group (RR 1·53, 0·88-2·62, p=0·130). INTERPRETATION: The results of this trial do not support inclusion of newborn vitamin A supplementation as a child survival strategy in Ghana. FUNDING: Bill & Melinda Gates Foundation grant to the WHO.

International experiences in assessing vitamin A status and applying the vitamin A-labeled isotope dilution method.

Inadequate vitamin A (VA) nutrition continues to be a major problem worldwide, and many interventions being implemented to improve VA status in various populations need to be evaluated. The interpretation of results after an intervention depends greatly on the method selected to assess VA status. To evaluate the effect of an intervention on VA status, researchers in Cameroon, India, Indonesia, Mexico, Senegal and Zambia have used serum retinol as an indicator, and have not always found improvement in response to supplementation. One problem is that homeostatic control of serum retinol may mask positive effects of treatment in that changes in concentration are observed only when status is either moderately to severely depleted or excessive. Because VA is stored mainly in the liver, measurements of hepatic VA stores are the “gold standard” for assessing VA status. Dose response tests such as the relative dose response (RDR) and the modified relative dose response (MRDR), allow a qualitative assessment of VA liver stores. On the other hand, the use of the vitamin A-labeled isotope dilution (VALID) technique, (using 13C or 2H-labeled retinyl acetate) serves as an indirect method to quantitatively estimate total body and liver VA stores. Countries including Cameroon, China, Ghana, Mexico, Thailand and Zambia are now applying the VALID method to sensitively assess changes in VA status during interventions, or to estimate a population’s dietary requirement for VA. Transition to the use of more sensitive biochemical indicators of VA status such as the VALID technique is needed to effectively assess interventions in populations where mild to moderate VA deficiency is more prevalent than severe deficiency.

Impact of vitamin A with zinc supplementation on malaria morbidity in Ghana.

BACKGROUND: Malaria is a leading cause of morbidity and mortality among young children and is estimated to cause at least 1 million deaths each year especially among pregnant women and young children under the age of five years. Vitamin A supplementation is known to reduce morbidity and mortality in young children. Zinc is required for growth and immunity and we sought to replicate the study by Zeba et al. which showed 30% lower cases of clinical malaria in children on a combination of zinc and a large dose of vitamin A compared with children on vitamin A alone based on the hypothesis that combined vitamin A and zinc reduced symptomatic malaria compared to vitamin A alone. OBJECTIVES: The primary objective was to determine the effect of vitamin A alone vs. vitamin A and zinc supplements on the incidence of clinical malaria and other anthropometric indices. It also sought to assess the effects on the incidence of anaemia, diarrhoea and pneumonia. METHODS: The study was community-based and 200 children between the ages of 6-24 months were randomised to receive either vitamin A (100,000 IU for infants less than 12 months & 200,000 IU for children greater than 12 months and 10 mg daily zinc in the intervention group or vitamin A and zinc placebo for 6 months in the control group. RESULTS: The number of children who were diagnosed with uncomplicated malaria in the intervention group was 27% significantly lower compared with the children in the control group (p = 0.03). There were, however, no effects on severe malaria, pneumonia, anaemia and diarrhea. CONCLUSIONS: Our study confirms a significant role of vitamin A and zinc in reducing malaria morbidity.

Efficacy of early neonatal vitamin A supplementation in reducing mortality during infancy in Ghana, India and Tanzania: study protocol for a randomized controlled trial.

BACKGROUND: Vitamin A supplementation of 6-59 month old children is currently recommended by the World Health Organization based on evidence that it reduces mortality. There has been considerable interest in determining the benefits of neonatal vitamin A supplementation, but the results of existing trials are conflicting. A technical consultation convened by WHO pointed to the need for larger scale studies in Asia and Africa to inform global policy on the use of neonatal vitamin A supplementation. Three trials were therefore initiated in Ghana, India and Tanzania to determine if vitamin A supplementation (50,000 IU) given to neonates once orally on the day of birth or within the next two days will reduce mortality in the period from supplementation to 6 months of age compared to placebo. METHODS/DESIGN: The trials are individually randomized, double masked, and placebo controlled. The required sample size is 40,200 in India and 32,000 each in Ghana and Tanzania. The study participants are neonates who fulfil age eligibility, whose families are likely to stay in the study area for the next 6 months, who are able to feed orally, and whose parent(s) provide informed written consent to participate in the study. Neonates randomized to the intervention group receive 50,000 IU vitamin A and the ones randomized to the control group receive placebo at the time of enrollment. Mortality and morbidity information are collected through periodic home visits by a study worker during infancy. The primary outcome of the study is mortality from supplementation to 6 months of age. The secondary outcome of the study is mortality from supplementation to 12 months of age. The three studies will be analysed independent of each other. Subgroup analysis will be carried out to determine the effect by birth weight, sex, and timing of DTP vaccine, socioeconomic groups and maternal large-dose vitamin A supplementation. DISCUSSION: The three ongoing studies are the largest studies evaluating the efficacy of vitamin A supplementation to neonates. Policy formulation will be based on the results of efficacy of the intervention from the ongoing randomized controlled trials combined with results of previous studies.

Seroprotection associated with infant vitamin A supplementation given with vaccines is not related to antibody affinity to Hepatitis B and Haemophilus influenzae type b vaccines.

Vaccines are usually assessed by analyses of their safety and immunogenicity to determine the effectiveness of eliciting antibody responses against target organisms. However, it is equally important to establish antibody affinity because of its specific role in protection from infection. Antibody affinity can be determined by comparisons of various antibody concentrations in dose-response curves. During a study on the immunogenicity of a pentavalent vaccine in 888 infants, antibody affinity analyses of the hepatitis B and Haemophilus influenzae type b components were investigated in infants given 15mg RE vitamin A with their vaccination and those who were not given vitamin A. In this paper we present the results of 222 infants; a 25% sub-sample of the original study. Analyses were carried out using dilutions of serum samples from fitted values corresponding to optical densities from antibody detection assays. These were obtained from the ligand binding equation and mid point titres in dose-response curves were then calculated. Vitamin A supplementation had no effect on the midpoint titres of Hepatitis B and H. influenzae type b vaccine derived antibodies. The significant effect of vitamin A supplementation on the Hepatitis B vaccine component observed in a previous seroprotection analysis is probably due to the amount of antibodies since affinity was unaffected.

Drawing blood from young children: lessons learned from a trial in Ghana.

This paper reflects on lessons learned from a trial in Ghana assessing the impact of vitamin A supplementation on children's immune responses to tetanus and polio vaccines. There were more losses to follow-up than was anticipated at visits during which blood was drawn, owing to concerns or misconceptions about blood draw. The trial initially planned to recruit 960 children but had to recruit more because the proportion of infants lost to follow-up was greater than the anticipated 15%, resulting in a longer recruitment period. Of 1085 infants who were randomised into the trial, 767 (71%) completed follow-up at 6 months of age. It was notable that at the first (6 weeks) and fourth (6 months) visits at which blood was drawn, losses to follow-up were greater than at the second (10 weeks) and third (14 weeks) visits during which blood was not drawn. Losses to follow-up pose a threat to the validity of trials as there is a chance that those lost to follow-up may differ from those who remain in the trial. Monitoring losses to follow-up as they emerged and allowing mothers to witness the blood draw, as well as holding community meetings, helped to allay anxieties in the community.

Vitamin A supplements are well tolerated with the pentavalent vaccine.

The Expanded Programme on Immunisation provides an opportunity to deliver vitamin A supplements to young infants in order to improve their vitamin A status. However, concerns have been raised about the safety of administering high dose vitamin A supplements to infants less than 6 months of age in developing countries. A randomized controlled trial was carried out by the Kintampo Health Research Centre to assess the safety and immunogenicity of administering 15 mg retinol equivalent (RE)1 vitamin A alongside the pentavalent "diphtheria-polio-tetanus-Haemophilus influenzae b-hepatitis B vaccine" at 6, 10 and 14 weeks of age. All mothers received a post-partum supplement of 120 mg RE vitamin A as per national policy. Mothers of infants who had been vaccinated were visited 24 h after vaccination to assess the side effects of the vaccine. They were also interviewed about adverse events which may have occurred in the past 4 weeks since the child was vaccinated. There were significantly fewer reports of illnesses and fever in infants who had been given vitamin A compared to infants in the control group. The pentavalent vaccine was found to be tolerable when administered with vitamin A according to the WHO/EPI schedule for infant immunisation at 6, 10 and 14 weeks. There were few complaints made by the mothers of the children which were not thought to be related to giving vitamin A with the vaccines. There were six deaths in the trial, five in the intervention group and one in the control RR 4.65 (0.55-39.5), p = 0.12. Due to the high point estimate of 4.65, we wish to urge caution in administering high doses of vitamin A to young infants with the pentavalent vaccine at 6, 10 and 14 weeks of age.

Vitamin A supplementation enhances infants' immune responses to hepatitis B vaccine but does not affect responses to Haemophilus influenzae type b vaccine.

Vitamin A supplementation reduces child mortality and severe morbidity in less developed countries, and the Expanded Program on Immunization (EPI) offers an ideal opportunity to deliver supplements in developing countries. High-dose vitamin A supplementation has been shown to have no effect on the immunogenicity of oral polio vaccine, tetanus toxoid, pertussis, or on measles vaccine given at 9 mo, but a negative effect on measles vaccine administered at 6 mo and a potentiating effect on diphtheria vaccine. Its effect on the antibody response to hepatitis B and Haemophilus influenzae type b antigens has not yet been established. To assess these effects, the present trial was carried out in the Offinso district of Ghana; 1077 infants were enrolled shortly after birth and randomized either to receive or not to receive 15 mg retinol equivalent with vitamin A together with the pentavalent "diphtheria-polio-tetanus-Haemophilus influenzae b-hepatitis B" vaccine at 6, 10, and 14 wk of age. All mothers received a postpartum supplement of 120 mg retinol equivalent vitamin A as per national policy. Blood samples were taken from infants at 6 and 18 wk of age. The results are based on 888 infants (82.4%) who completed the trial. The vitamin A supplementation did not affect the immune response to Haemophilus influenzae type b, but there was a significant improvement in the immune response to hepatitis B vaccine (93.9 vs. 90.2%, P = 0.04). However, given the high percentage of infants with seroprotection in the control group, it is doubtful that inclusion of vitamin A in the EPI would be justified on these grounds alone.

Vitamin a supplementation does not affect infants' immune responses to polio and tetanus vaccines.

It has been suggested that administering vitamin A with the measles vaccine may reduce the vaccine's immunogenicity. This trial examined the effect of supplementing vitamin A during the early months of life on infants' immune responses to tetanus and polio vaccines. Young infants (n = 1085) were enrolled and individually randomized into 1 of 4 groups in a factorial, double-blind, placebo-controlled trial. Three vitamin A supplementation strategies were investigated: 1) supplementation of breast-feeding mothers with 60 mg retinol equivalent (RE) vitamin A within 4 wk of delivery; 2) Expanded Program on Immunization (EPI)-linked supplementation of infants with 7.5 mg RE vitamin A at 6, 10, and 14 wk; and 3) combined mother and child supplementations. A 4th group in which mother and child were given placebos served as controls. Blood samples were collected from each child at 6 wk and 6 mo of age to measure antipolio antibody titer, antitetanus toxoid antibodies, and avidity of antibodies to tetanus. Of the infants randomized into the 4 arms of the study, 767 (71%) completed follow-up at 6 mo of age. Follow-up rates were similar in all 4 arms (69-72%, P = 0.8). Antibody titers were relatively high in all 4 groups at both 6 wk and 6 mo of age, with no differences among the groups. We found no evidence that vitamin A supplementation affects infants' antibody responses to tetanus toxoid or oral polio vaccine delivered at EPI contacts.