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3 Kintampo Health Research Centre, Kintampo, Ghana; 4 London School of Hygiene and Tropical Medicine, London, UK; 5 Noguchi Memorial Institute for Medical Research, Accra, Ghana; and 6 Navrongo Health Research Centre, Navrongo, Ghana
* To whom correspondence should be addressed. E-mail: sam.newton{at}ghana-khrc.org.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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In 2002, the Ministry of Health in Ghana introduced the pentavalent, diphtheria-pertussis-tetanus (DPT), hepatitis B (HepB), and Haemophilus influenzae type b (Hib) vaccine into Ghana's immunization program in place of the conventional DPT vaccine while maintaining the immunization schedule at 6, 10, and 14 wk. Studies confirm that the administration of vitamin A at the time of vaccination has no negative effect on seroconversion to DPT (7–11) but it does reduce the antibody response to measles vaccine when given at 6 mo, when maternal antibodies tend to be high, rather than at the usual 9 mo (12). The effect of vitamin A on the antibody response to the hepatitis B and Haemophilus influenzae type b antigens has not yet been established, although countries with support from the Global Alliance for Vaccines and Immunization have started introducing these new vaccines into their EPI schedules. This trial was therefore carried out to assess these effects.
The objective of the trial was to compare the seroprotection rates and geometric mean antibody concentrations at 18 wk of age to hepatitis B and Hib vaccines in infants who received, along with their vaccines at 6, 10, and 14 wk, 15 mg of retinol equivalent8 vitamin A with those infants who did not receive vitamin A. We hypothesized that the simultaneous administration of vitamin A (an immune enhancer) and the pentavalent vaccine to young infants in EPI clinics would reduce or enhance the serological response to hepatitis B and Hib vaccines.
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Methods |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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The trial was an open randomized and controlled trial conducted by investigators from the Kintampo Health Research Center (KHRC). It was carried out in Akumadan, Afrancho, and Nkenkaasu, 3 towns in the Offinso District in the northern fringes of the Ashanti Region of Ghana, bordering the KHRC study area in the Brong Ahafo region. We estimated from an earlier study that >51% of children <5 y of age in this area have serum retinol concentrations 
0.70 µmol/L (5). A recent survey among pregnant women attending an antenatal clinic in Nkoranza district, 30 km from the study area, showed a 51% prevalence of vitamin A deficiency (13).
Participants
Trained field workers identified newborn infants through active weekly surveillance in the community. Mothers who gave signed or thumb-printed informed consent, had infants between the ages of 6 and 10 wk at the time of 1st vaccination, and intended to stay in the study area for the entire duration of the trial (i.e., until their infants reached 18 wk of age), were considered eligible for enrollment. Breast-feeding was virtually universal in this area (14), and the newly introduced pentavalent vaccine (DPT+Hep+Hib) was routinely given at 6, 10, and 14 wk of age in health facilities.
Ethical issues
Informed consent for participation was sought from all mothers after they were given a detailed explanation of the purpose of the study. The trial was approved by the Ethical Review Committees of the Ghana Health Service, the WHO, and the London School of Hygiene and Tropical Medicine.
Sample size
We determined that a sample size of 948 mother infant pairs was required to detect a difference in seroprotection rates from 95 to 90%, with 80% power at the 5% significance level. Including a provision of 10% loss to follow-up gave a requirement of 1042 mother-infant pairs.
Intervention groups
All infants were vaccinated with polio plus the pentavalent vaccine (DPT+Hib+Hep) at 6, 10, and 14 wk of age; they were given 2 drops (0.1 mL) of live, attenuated oral poliomyelitis vaccine (Sabin) [Polioral, Lot A0PVB170AA] directly into the mouth and were injected with 0.5 mL Tritanrix HB+Hiberix, which contained combined diphtheria-tetanus-toxoid whole cell pertussis bacteria (Pw), the purified major surface antigen of the hepatitis B virus, adsorbed onto aluminum salts and purified polyribosyl-ribitol-phosphate capsular polysaccharide of Hib, covalently bound to tetanus toxoid (GlaxoSmithKline Biologicals, Lot AH IBB133BA).
Infants in the intervention group also received an oral dose of 15 mg retinol equivalent vitamin A at the time they received their vaccines, whereas those in the control group did not. All infants were given 30 mg retinol equivalent vitamin A at the end of the trial at 18 wk of age after all blood samples had been collected.
Mothers in both groups received 120 mg retinol equivalent vitamin A, as retinol palmitate, as soon as possible postdelivery according to current government policy and following the recommendations of the International Vitamin A Consultative Group (that postpartum mothers receive vitamin A in order for their infants to benefit from increased vitamin A intake through breast-feeding) (15).
Randomization
Mothers and their infants were allocated to the intervention or control groups based on the date of birth of their infants. Those born during wk 1 of recruitment (15 June 2004) were assigned to the intervention group, those born the following week were assigned to the control group, those born the next week were assigned to the intervention group, and so on, until recruitment was completed. The infant's date of birth was carefully verified to make sure that mothers could not influence which group their infant would be placed in.
Trial procedures
All vaccinations and vitamin A dosing were carried out in the clinic by community health nurses. Each week, listings of infants due for immunization the following week were generated from a computerized database of enrolled infants and were given to field workers who reminded mothers that an immunization visit was due. Study infants were identified at the clinic using trial ID cards by trained trial staff prior to immunization. If any infants were not brought to the clinic, fieldworkers made another reminder call to the home.
At the 1st EPI contact, i.e., at 6 wk of age and after the administration of vaccines, KHRC laboratory staff collected a 1 mL blood sample by heel prick from all infants whose mothers had given consent at enrollment to the measurement of antibodies to hepatitis B and Haemophilus influenzae type b. Another 1 mL blood sample was taken at the final 18 wk of age follow-up, and then all infants were given 30 mg retinol equivalent vitamin A.
Blinding
The study was not blinded because placebos could not be given to the control group due to logistical and cost constraints. However, the measurement of trial outcomes was blinded; blood samples sent to the laboratory for analysis were identified by ID number only, and the laboratory was blinded as to what samples belonged to what group.
Blood collection and antibody analyses
The blood samples were centrifuged at 1400 x g for 10 min at the KHRC laboratory in Kintampo and stored in aliquots at –20°C before being transported to the Noguchi Memorial Institute for Medical Research (NMIMR) at the University of Ghana for analysis for hepatitis B and Haemophilus influenzae type b antibodies, using standard ELISA tests.
ELISA for anti-Hib antibody determination. BINDAZYME Anti Haemophilus influenzae type B enzyme immunoassay kit, manufactured by Binding Site,was used. This assay is for the in-vitro measurement of specific IgG antibodies against Hib capsular polysaccharide, which is present in human sera. The assay has been found to be reproducible, consistent, and reliable and was chosen because it is more convenient than the standard, radio antigen binding assays (RABA) for the measurement of anti-Hib. ELISA has been shown to correlate well with the RABA assays and allows the selective quantification of the IgG isotype (16,17). Serum anti-Hib antibodies protect against the organism in-vivo, and protective levels have been established for unvaccinated and vaccinated individuals by RABA (18). The kit uses microplates coated with Hib capsular polysaccharide antigen conjugated to human serum albumin. Purified peroxidase labeled rabbit anti-human lgG was used as the enzyme conjugate with 3, 3', 5, 5' tetramethylbenzidine (TMB) as the substrate (19).
ELISA for anti-HepB antibody determination. EQUIPAR HBsAb enzyme immunoassay, manufactured by Equipar SRI, was used. This assay is for the quantitative determination of antibodies to hepatitis B virus. The kit uses microplates coated with a preparation of highly purified Hep B antigen. Following the addition of samples and subsequent washing, a different Hep B antigen conjugated to peroxide was added that binds to a 2nd site on the antibody. The enzyme specifically binds to wells by acting on the substrate/chromogen mixture, generating an optical signal proportional to the amount of Hep B antibodies in the sample and detectible by an ELISA reader. The concentration of antibodies is then estimated by means of a standard curve calibrated against the WHO reference preparation (20).
Outcomes
The impact of vitamin A supplementation was assessed by comparing treatment groups with respect to seroprotection rates and geometric mean antibody concentrations for hepatitis B and Hib at 18 wk of age and following a full course of 3 doses of vaccines at 6, 10, and 14 wk of age. Two levels were used for assessing seroprotection to Hib: a level of 
0.15 µg/mL for short-term protection, and 1.0 µg/mL for long-term protection (21,22). For hepatitis B seroprotection level was defined as 10 mIU/mL (23).
Data management and statistical methods
Microsoft Access data management software was used for data entry and Stata software, version 7, was used for the analyses. All data were doubly entered on computers, range and consistency checks performed, and discrepancies resolved. All analyses were based on the infants who successfully completed all stages of the trial and received all 3 doses of vaccines plus all 3 doses of vitamin A (if in the vitamin A group) and on those who received just the vaccines (if in the control group) and gave blood samples at 6 wk and 18 wk.
Baseline comparability between the treatment groups, those completing the trial, and those lost to follow-up, was assessed by a simple tabulation of means for numerical variables and percentages for categorical variables.
Antibody responses to Haemophilus influenzae B and hepatitis B were assessed against standard cut-off levels as follows: 2 levels were used for Haemophilis influenzae type b, 0.15 µg/mL indicating short-term protection and 1.0 µg/mL indicating long-term protection; and one cut-off, 10.0 mIU/mL, was used to indicate protection against hepatitis B. The percentages of infants with adequate seroprotection levels in the vitamin A and control groups were compared using simple chi-squared tests, and the results were presented as relative risks with 95% CI. The geometric mean concentrations (GMC) of antibody levels were also assessed and compared between the treatment groups. These analyses were carried out by calculating the relevant means of logarithmically transformed antibody concentrations, i.e., those that were reported below the assay cut-off given an arbitrary value equal to one-half of the assay cut-off. The means were compared at 6 and 18 wk using Student t tests and then anti-logged to give GMC. The GMC were reported with their 95% CI. Infants' antibody responses were also compared at 18 wk of age, and data were analyzed using multiple linear regression after adjustment for baseline levels. Differences were considered significant at P < 0.05.
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Results |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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4 wk postpartum), but before the child received any vaccines or doses of vitamin A.
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Impact of vitamin A on antibody responses.
The overall antibody response to the Hib vaccine was high and was not influenced by the simultaneous administration of vitamin A. At 18 wk of age, 98% of infants in both the vitamin A and control groups had levels of antibody higher than the minimum cut-off (0.15 µg/mL) for short-term protection, and 94% had levels 1.0 µg/mL, indicating long-term protection (Table 2).
More infants in the vitamin A group had an increased antibody response to hepatitis B (10 mIU/mL) than in the control group, although the increase was marginal (Table 2); the response rates in both groups were high (93.9 vs. 90.2%, P = 0.04). This finding was unchanged when the analysis was repeated with the adjustment for baseline antibody levels.
There was no evidence of any differential impact on the geometric mean concentrations of the antibody responses to the vaccines (Table 3).
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Discussion |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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At 6 wk of age, 76% of infants in our study had levels of antibody for Haemophilus influenzae type b 0.15 µg/mL, which is the threshold conferring short-term protection. This indicates that a high percentage of infants had maternal antibodies (IgG), which is considerably higher than the 43.7% reported by Hussey et al. (24) in 6-wk–old infants of Cape Town. Our short-term protection response rate of 98% at 18 wk after 3 doses of vaccine is similar to that reported by Hussey et al. (24) in Cape Town and Win et al. (25) in Burma. Although a significantly higher proportion of infants in the vitamin A group met the long-term threshold (1 µg/mL) at baseline, this difference is unlikely to have affected our 18-wk response rates after vaccination. The antibodies present at 6 wk of age are mainly maternal antibodies, which are not relevant for long-term protection of the infant and do not last long (24). The 18-wk response rates indicate that infants' own antibodies increased in response to the 3 doses of vaccines. These rates were high (94%) and did not differ between the vitamin A and control groups; they were similar to those found in studies carried out by Watemberg et al. (26) in Israel and Capeding et al. (27) in Philippines.
Hepatitis B virus infection is highly endemic in Ghana as demonstrated by a high rate, i.e., 15% of hepatitis B–infected blood donors following blood screening (28). At 6 wk of age, 10.8% of infants in our study had seroprotection to hepatitis B 10 mIU/mL, indicating the presence of maternal IgG immunoglobulin.
In our study, at 18 wk of age, 94% of infants supplemented with vitamin A were seroprotected to hepatitis B compared with 90% in the control group (P = 0.04). Neither group achieved the WHO recommendation, which states that, for effective immunization, seroprotection rates for hepatitis B vaccine must exceed 95% (29). However, we could not locate comparable studies that assessed seroprotection to hepatitis B 1 mo after the 3rd vaccine dose, 14 wk EPI vaccine, had been given. Our study was not designed to look at complex mechanisms that might explain the differences between groups, but, considering that vitamin A is an immune enhancer, minor changes in the immune response to the hepatitis B vaccine could have occurred.
Semba et al. (12) observed significant suppression of seroconversion rates to the measles vaccine in Indonesian infants 6 mo of age when maternal antibody was high. They hypothesized that immune enhancement by vitamin A might limit the ability of live viruses, such as the measles vaccine, to establish infection; although others have attributed the observation to the type of measles vaccine used (the Schwarz vaccine) (30). In contrast, in Guinea Bissau, immunogenicity of the measles vaccine given to 6-mo–old infants carrying the maternal antibody was enhanced after administration of high doses of vitamin A (31), a phenomenon we observed in our study with hepatitis B. The administration of vitamin A to infants at 6, 10, and 14 wk of age, at the same time as they received oral polio vaccine, which, like measles, is a live vaccine, did not interfere with the immune response to any of the 3 polioviruses and was associated with an enhanced response to poliovirus type 1 (32).
The number of mother-infant pairs that finally completed the study was 888, less than the 948 required to detect a difference in seroprotection rates from 95 to 90% between the groups. The 888 mother-infant pairs that we finally obtained were higher than the 704 required to detect a 6% difference in seroprotection. Other investigators, including Bahl et al. (32) and Aristegui et al. (33), recruited infants with sample sizes based on a 15% difference between groups. We therefore think that our estimated 5% difference gave us a sample size that was too high, and that this study could have been carried out with fewer subjects.
In our study, there was a good immune response to both vaccines. There was no impact of vitamin A supplementation on the Haemophilus influenzae type b component of the pentavalent vaccine; but, even though there was an improvement in the immune response to the hepatitis B vaccination (93.9 vs. 90.2%), the difference was small. However, given the high percentage of infants with seroprotection in the control group, it is doubtful that including vitamin A in the EPI would be justified on these grounds alone.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Author disclosures: S. Newton, no conflicts of interest; S. Owusu-Agyei, no conflicts of interest; W. Ampofo, no conflicts of interest; C. Zandoh, no conflicts of interest; M. Adjuik, no conflicts of interest; G. Adjei, no conflicts of interest; S. Tchum, no conflicts of interest; S. Filteau, no conflicts of interest; and B. R. Kirkwood, no conflicts of interest.
7 Abbreviations used: DPT, diphtheria, pertussis, tetanus; EPI, Expanded Program on Immunization; GMC, geometric mean concentration; Hep B, hepatitis B; Hib, Haemophilus influenzae type b; RABA, radio antigen binding assay.
8 120 mg retinol equivalent (400,000 IU); 15 mg retinol equivalent (50,000 IU).
Manuscript received 13 December 2006. Initial review completed 8 January 2007. Revision accepted 13 February 2007.
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