Akib, A

Mohgaddam, NEG

Muherdiyantiningsih, -

Muhilal, -

Munasir, Z

Osterhaus, Ab

Permaesih, D

Semba, RD

English

EUR Research Repository

Community and International NutritionResearch CommunicationIntegration of Vitamin ASupplementation with theExpanded Program onImmunization Does NotAffect Seroconversion toOral Poliovirus Vaccinein Infants1Richard D. Semba,2 Muhilal,* Nasrin E. G. Mohgaddam,†Zakiuddin Munasir,** Arwin Akib,** Dewi Permaesih,*Muherdiyantiningsih* and Albert Osterhaus‡Department of Ophthalmology, School of Medicine, JohnsHopkins University, Baltimore, MD 21287; *Nutrition Research andDevelopment Centre, Ministry of Health, Bogor, Indonesia;†National Institute of Public Health and the Environment,Bilthoven, The Netherlands; **Department of Paediatrics and ChildHealth, University of Indonesia, Jakarta, Indonesia; and‡Department of Virology, Erasmus University, Rotterdam,The NetherlandsABSTRACT Childhood immunization programs may pro-vide infrastructure for delivering vitamin A supplements toinfants in developing countries. The effect of giving vitaminA, an immune enhancer, on antibody responses to trivalentoral poliovirus vaccine (TOPV) is unknown. A randomized,double-blind, placebo-controlled clinical trial was con-ducted to determine the effect of giving vitamin A simulta-neously with TOPV on antibody responses to poliovirus.Infants (n 5 467) received oral vitamin A, 15 mg retinolequivalent (RE), 7.5 mg RE or placebo with TOPV at 6, 10and 14 wk of age. Antibody responses to poliovirus types 1,2 and 3 were measured by a microvirus neutralization assayat enrollment and at 9 mo of age. Seroconversion rates topoliovirus types 1, 2 and 3 ranged from 98 to 100% in thethree treatment groups, and there were no differences inmean antibody titers to poliovirus types 1, 2 and 3 amongtreatment groups. This study demonstrates that oral vita-min A does not affect antibody responses to poliovirusvaccine when integrated with the Expanded Program onImmunization. J. Nutr. 129: 2203–2205, 1999.KEY WORDS: ● infants ● vitamin A ● immunization● poliovirus ● vaccineVitamin A deficiency is a major cause of childhood mor-bidity and mortality in developing countries (Sommer andWest 1996). Periodic high dose vitamin A supplementationhas been shown to reduce child mortality by about one third(Beaton et al. 1993). The infrastructure of childhood immu-nization programs involves an estimated 500 million childcontacts per year; it has been suggested that this infrastructurecould be used for the delivery of micronutrient supplements toinfants [Expanded Program on Immunization (EPI)3 GlobalAdvisory Group 1987]. Vitamin A, through its active metab-olites, controls the transcriptional activation of many genes, isa potent modulator of many different pathways in the immunesystem and is known to influence responses to vaccination(Semba 1998). Oral high dose vitamin A given simultaneouslywith standard titer Schwarz measles vaccine may interfere withseroconversion to the measles virus in 6-mo-old infants whohave high levels of maternal antibody to measles virus (Sembaet al.1995), but not in 9-mo-old infants who have low levels orno maternal antibody to measles virus (Benn et al. 1997,Semba et al. 1997). Trivalent oral poliovirus vaccine (TOPV)is also a live attenuated vaccine, and there is concern that oralvitamin A could interfere with seroconversion to TOPV whengiven simultaneously in childhood immunization programs.We conducted a randomized, double-blind, placebo-controlledclinical trial to determine the effect of simultaneous vitamin Aadministration on antibody responses to TOPV in infants.SUBJECTS AND METHODSThe study population consisted of infants in 27 villages in BogorDistrict, West Java, Indonesia, an area with a high prevalence of sub-clinical vitamin A deficiency (Semba 1995). After written, informedconsent was obtained from the mother or father, infants were enrolled inthe clinical trial between October 1992 and February 1993. Details ofthis clinical trial have been described elsewhere (Semba et al. 1997).Infants were randomly allocated by number table in blocks of 10 toreceive 15 mg retinol equivalent (RE), 7.5 mg RE of vitamin A orplacebo at 6, 10 and 14 wk of age. At age 6, 10 and 14 wk, infantsreceived TOPV [Polioral, Biocine Sclavo, Siena, Italy, lot 73A12, 1.15mL volume, tissue culture dose 50% infectivity (TCID50) for type 1, 2and 3: 106.0, 105.0, and 105.8, respectively] and diphtheria-pertussis-tetanus vaccine (Biofarma, Bandung, Indonesia) administered by a pe-diatrician. Vitamin A and placebo solutions were dispensed from amberglass micronutrient dispensers (Swift dispensers, Englass, Leicester, U.K.)within 10–30 min after TOPV immunization. TOPV was not adminis-tered to the infants at birth. The cold chain was extensively monitoredduring shipping from the factory in Siena, Italy to the study laboratory inBogor, Indonesia using temperature-sensitive monitors. All infants wereseen and examined by a pediatrician at each visit. At the time oftreatment allocation, both the pediatrician and study nurse were requiredto verify the identification number of the infant. Height, weight, midupper-arm circumference and head circumference were measured by awell-trained anthropometrist when the infants were 6 and 14 wk of age.1 Supported by grants from the Thrasher Research Fund, the World HealthOrganization Expanded Programme on Immunization, the National Institutes ofHealth (AI35143), and the U.S. Agency for International Development (Coopera-tive Agreement DAN-0045-A-5094–00).2 To whom correspondence should be addressed.3 Abbreviations used: EPI, Expanded Program on Immunization; RE, retinolequivalent; TCID50 tissue culture dose, 50% infectivity; TOPV, trivalent oral po-liovirus vaccine.0022-3166/99 $3.00 © 1999 American Society for Nutritional Sciences.Manuscript received 23 April 1999. Initial review completed 20 June 1999. Revision accepted 24 August 1999.2203 at Erasmus Rotterdam 42300.7802.430 / BIN 8025 on January 6, 2009 jn.nutrition.orgDownloaded from Blood was obtained by venipuncture at 6 and 14 wk, and 9 mo ofage, and plasma was separated and frozen at 270°C. Plasma vitaminA levels were measured by HPLC at 6 and 14 wk (Semba et al. 1997).Antibody titers to poliovirus serotypes were measured by a microvirusneutralization assay (Kapsenberg et al. 1981) and were standardizedagainst poliovirus reference sera (World Health Organization, Ge-neva, Switerland). Seroconversion to poliovirus was defined as apositive antibody titer at 9 mo of age ($2), minus the calculatedexpected titer of passively acquired maternal antibody to poliovirus,assuming a half-life of immunoglobulin G to be 4 wk. The virusneutralizing antibody level considered to be consistent with protec-tion against poliovirus at 9 mo of age was $8 (WHO Expert Com-mittee on Biological Standardization 1988). Categorical analyseswere conducted using x-square and exact tests. Student’s and Bon-ferroni’s t tests were used for appropriate comparisons of continuousdata. A paired t test was used to compare plasma vitamin A levels atbaseline and follow-up. The study protocol was approved by theethical review committees at the Johns Hopkins School of Medicine,the Ministry of Health, Government of Indonesia, and the WHOSecretariat Committee on Research Involving Human Subjects.RESULTSThere were 467 infants enrolled in the study at age 6 wk.Follow-up rates of the infants to 10 and 14 wk and 9 mo were93.6, 91.6 and 84.5%, respectively. Characteristics of infantsin the three treatment groups are shown in Table 1. Therewere no significant differences in weight, height or otheranthropometric measurements at baseline. Antibody titers topoliovirus were measured in 353 of 394 infants who were seenboth at enrollment and at 9 mo of age. Plasma samples wereunavailable for 41 infants because of insufficient sample vol-ume. Seroconversion rates to the three poliovirus types bytreatment group are shown in Table 2. The rates of serocon-version were 97–100%, with no significant differences amongtreatment groups in seroconversion to any of the three polio-virus types. The proportion of infants with titers $8, a levelconsidered to confer protection against poliovirus, is shown inTable 2. The proportion of infants with protective titersagainst the three respective polioviruses ranged from 93.1 to99.1%, with no significant differences in protection amongtreatment groups. Loge antibody titers to the three poliovirustypes did not differ by treatment group (Table 3). There wereno significant differences in geometric mean titers to any ofthe poliovirus types among treatment groups. There were nocases of polio among the infants in the study during follow-up.DISCUSSIONThis study shows that vitamin A supplementation givenconcurrently with TOPV immunization at the 6-, 10- and14-wk visits of the Expanded Program on Immunization doesTABLE 1Characteristics of mothers and infants in Indonesia by allocation groupCharacteristic1,2Placebo(n 5 156)Vitamin A 7.5 mg RE(n 5 156)Vitamin A 15 mg RE(n 5 155)Maternal age, y 26.5 6 0.5 26.2 6 0.5 26.0 6 0.5Infant age, d 53.8 6 0.8 53.1 6 0.8 52.7 6 0.9Infant gender 82 M, 74 F 88 M, 68 F 86 M, 69 FWeight, kg 4.75 6 0.06 4.65 6 0.05 4.74 6 0.05Height, cm 55.8 6 0.2 55.8 6 0.2 55.9 6 0.2Mid upper-arm circumference, cm 12.55 6 0.08 12.35 6 0.09 12.56 6 0.09Head circumference, cm 37.7 6 0.1 37.5 6 0.1 37.7 6 0.2Plasma retinol, baseline, mmol/L 0.61 6 0.01 0.61 6 0.01 0.61 6 0.01Plasma retinol, 14 wk, mmol/L 0.64 6 0.01 0.73 6 0.023 0.76 6 0.023Plasma retinol ,0.35 mmol/L at baseline, % 10.97 11.04 10.97Plasma retinol ,0.35 mmol/L at 14 wk, % 7.19 1.40 1.3841 No significant difference was noted among groups for all characteristics shown, except for plasma retinol at 14 wk. Plasma retinol was measuredin 139, 143, and 145 subjects of placebo, 7.5 mg retinol equivalent (RE), and 15 mg RE vitamin A groups at 14 wk, respectively.2 For continuous variables, mean 6 SEM.3 Paired t test, difference in plasma retinol between baseline and 14 wk, P , 0.0001.4 Vitamin A–supplemented groups different from placebo by Mantel-Haenszel x-square, P , 0.006.TABLE 2Seroconversion rates and protection against poliovirus types 1, 2, 3 in Indonesian infantsPoliovirus PlaceboVitamin A(25,000 IU)Vitamin A(50,000 IU) P-valueSeroconversion1Type 1 91/92 (98.9%) 109/110 (99.1%) 100/102 (98.0%) 0.77Type 2 113/113 (100%) 124/124 (100%) 116/116 (100%) 1.00Type 3 111/112 (99.1%) 122/122 (100%) 113/113 (100%) 0.99Protection2Type 1 87/92 (94.5%) 104/110 (94.5%) 95/102 (93.1%) 0.88Type 2 112/113 (99.1%) 122/124 (98.4%) 114/116 (98.3%) 0.84Type 3 108/113 (95.6%) 121/123 (98.3%) 111/115 (96.5%) 0.451 Detectable neutralizing antibody titer at 9 mo of age, adjusting for half-life of maternal antibody titer at enrollment.2 Antibody titer $8 at follow-up visit at 9 mo of age (World Health Organization Expert Committee on Biological Standardization 1988).SEMBA ET AL.2204 at Erasmus Rotterdam 42300.7802.430 / BIN 8025 on January 6, 2009 jn.nutrition.orgDownloaded from not interfere with seroconversion to any of the three poliotypes. In addition, there were no significant differences amongthe three treatment groups in the proportion of infants whohad antibody titers considered protective against polio and inthe mean antibody titers against the three polio types. In adifferent but related study design, vitamin A supplementationto mothers but not their infants did not interfere with sero-conversion to oral poliovirus vaccine (Bhaskaram and Bal-akrishna 1998). Vitamin A supplementation given at the timeof measles immunization has been shown to interfere withantibody responses to measles in infants with high levels ofmaternal antibody, but not in infants with little to no mater-nal antibody to measles (Benn et al. 1997, Semba et al. 1995and 1997). The mode of delivery of vaccine (oral vs. subcu-taneous) and type of virus may account for some of thedifferences between possible effects of vitamin A on immuneresponses to vaccination.Although TOPV is generally considered effective, thisstudy shows that it is possible to have higher rates of serocon-version and protection than those generally reported fromdeveloping countries using TOPV (Patriarca et al. 1991).Factors that might affect the efficacy of TOPV include thevaccine potency, vaccine stability, age at first dose, the inter-val between doses and dosage volume. The TOPV used in thisstudy met the requirements for potency developed by theExpert Committee on Biologic Standardization (WHO ExpertCommittee 1988), and the cold chain was strictly monitoredfrom the factory until the moment it was administered in theclinic. The age at first dose and interval between doses fol-lowed the guidelines of the EPI. This study suggests that strictadherence to WHO guidelines for potency and administrationof TOPV can result in high rates of seroconversion and pro-tection from polio in a developing country such as Indonesia.Infancy is a high risk period for the development of micro-nutrient deficiencies in many developing world populations,and the integration of vitamin A supplementation with theEPI, in addition to periodic high dose vitamin A supplemen-tation for preschool children, is proceeding in some countriesin which vitamin A deficiency is a public health problem.Integration of vitamin A supplementation with the EPI im-proves vitamin A status of infants but seems to have no effecton infant morbidity and mortality (WHO/CHD Immunisa-tion-Linked Vitamin A Supplementation Study Group 1998).The infrastructure of the EPI also offers the opportunity tosupplement infants with oral iodized oil. In Indonesia, infantsreceiving oral iodized oil capsules given through the EPI at 6wk of age had lower mortality rates, presumably because of aneffect of oral iodized oil on thyroid status and immunity(Cobra et al. 1997). In the same trial, oral iodized oil did notinterfere with seroconversion to TOPV when given throughthe EPI (Taffs et al. 1999).This study suggests that oral vitamin A supplementationcan be integrated with the EPI without an adverse effect onantibody responses to oral poliovirus vaccine and that highseroconversion rates can be achieved with careful monitoringof the cold chain. Integration of vitamin A with the EPIshould be considered in countries in which clinical and sub-clinical vitamin A deficiency is endemic.ACKNOWLEDGMENTSThe authors wish to acknowledge the staff of the Nutrition Re-search and Development Center and D. Jut of the National Instituteof Public Health and the Environment, Bilthoven, The Netherlands.We thank Biocine Sclavo, Siena, Italy, for donation of oral poliovirusvaccine, Task Force Sight and Life, Basel, for donation of vitamin A,and Englass, Leicester, England for donation of micronutrient dis-pensers.LITERATURE CITEDBeaton, G. H., Martorell, R., L’Abbé, K. A., Edmonston, B., McCabe, G., Ross,A. C. & Harvey, B. (1993) Effectiveness of vitamin A supplementation in thecontrol of young child morbidity and mortality in developing countries. ACC/SCN State-of-the-Art Nutrition Policy Discussion Paper no. 13, United Na-tions, New York, NY.Benn, C. S., Aaby, P., Balé, C., Olsen, J., Michaelsen, K. F., George, E. & Whittle,H. (1997) Randomised trial of effect of vitamin A supplementation onantibody response to measles vaccine in Guinea-Bissau, west Africa. Lancet350: 101–105.Bhaskaram, P. & Balakrishna, N. (1998) Effect of administration of 200,000 IUof vitamin A to women within 24 hrs after delivery on response to PPVadministered to the newborn. Indian Pediatr. 35: 217–222.Cobra, C., Muhilal, Rusmil, K., Rustama, D., Djatnika, Suwardi S. S., Permaesih,D., Muherdiyantininsih, Martuti, S. & Semba, R. D. (1997) Infant survival isimproved by oral iodine supplementation. J. Nutr 127: 574–578.Expanded Programme on Immunisation Global Advisory Group (1987) WHOWkly. Rec. 62: 5–12.Kapsenberg, J. G., Coutinho, R. A., Hazendonk, A. G., Ran, A.B.R. & van Wezel,A. L. (1981) Epidemiological implications of the isolations and intratypicserodifferentiation of poliovirus strains in the Netherlands. Dev. Biol. Stand.47: 293–301.Patriarca, P. A., Wright, P. F. & John, T. J. (1991) Factors affecting theimmunogenicity of oral poliovirus vaccine in developing countries: review.Rev. Infect. Dis. 13: 926–939.Semba, R. D. (1998) The role of vitamin A and related retinoids in immunefunction. Nutr. Rev. 56: S38–S48.Semba, R. D., Akib, A., Beeler, J., Munasir, Z., Permaesih, D., Muherdiyantininsih,Komala, Martuti, S. & Muhilal (1997) Effect of vitamin A supplementationon measles vaccination in nine-month-old infants. Public Health 111: 245–247.Semba, R. D., Munasir, Z., Beeler, J., Akib, A., Muhilal, Audet, S. & Sommer, A.(1995) Reduced seroconversion to measles in infants given vitamin A withmeasles vaccination. Lancet 345: 1330–1332.Sommer, A. & West, K. P., Jr. (1996) Vitamin A Deficiency: Health, Survival,and Vision. Oxford University Press, New York, NY.Taffs, R. E., Enterline, J. C., Rusmil, K., Muhilal, Suwardi, S. S., Rustama, D.,Djatnika, Cobra, C., Semba, R. D., Cohen, N. & Asher, D. M. (1999) Oraliodine supplementation does not reduce neutralizing-antibody responses tooral poliovirus vaccine. Bull. WHO 77: 484–491.World Health Organization Expert Committee on Biological Standardization(1988) 38th Report, Tech. Rep. Series no. 771. WHO, Geneva, Switzerland.WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group.(1998) Randomised trial to assess benefits and safety of vitamin A supple-mentation linked to immunisation in early infancy. Lancet 352: 1257–1263.TABLE 3Loge antibody titers against poliovirus types 1, 2, 3in 9-mo-old Indonesian infants1,2Poliovirus PlaceboVitamin A 7.5 mgREVitamin A 15 mgREType 1 5.26 6 0.16 [92] 5.63 6 0.16[110] 5.32 6 0.17[102]Type 2 5.95 6 0.12[113] 6.02 6 0.12[124] 5.96 6 0.11[116]Type 3 5.36 6 0.14[113] 5.44 6 0.12[123] 5.21 6 0.12[115]1 No significant differences noted between allocation groups.2 n in each group in brackets.RE, retinol equivalent.VITAMIN A AND SEROCONVERSION TO POLIO VACCINE 2205 at Erasmus Rotterdam 42300.7802.430 / BIN 8025 on January 6, 2009 jn.nutrition.orgDownloaded from 

Integration of vitamin A supplementation with the expanded program on immunization does not affect seroconversion to oral poliovirus vaccine in infants

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Integration of vitamin A supplementation with the expanded program on immunization does not affect seroconversion to oral poliovirus vaccine in infants

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