A double blind randomized controlled trial in neonates to determine the effect of vitamin A supplementation on immune responses: The Gambia protocol

Suzanna L R McDonald, Mathilde Savy, Anthony J C Fulford, Lindsay Kendall, Katie L Flanagan, Andrew M Prentice, Suzanna L R McDonald, Mathilde Savy, Anthony J C Fulford, Lindsay Kendall, Katie L Flanagan, Andrew M Prentice

Abstract

Background: Vitamin A supplementation significantly reduces all-cause mortality when given between 6-59 months of age, but has a null or detrimental effect when given between 1-5 months. Studies of neonatal vitamin A supplementation conducted across Africa and South Asia have produced conflicting findings. These age-pattern variations might result from immunological interactions between vitamin A supplementation and vaccines. Knowledge on the potential immunological sequelae of human neonatal vitamin A supplementation is so scarce that the foremost aim of this study is to seek indicative data on aspects of immunity likely to be affected by neonatal vitamin A supplementation. The objective of this trial is to test whether human neonatal vitamin A supplementation modulates immune function including improved thymic maturation in infancy and improved systemic immune responses to routine immunization.

Methods/design: In an area of moderate vitamin A deficiency in a peri-urban area of The Gambia, 200 mother-infant pairs were enrolled in a double-blind randomised controlled trial. Within 48 hours of birth, neonates were randomised with stratification by birth weight and sex to receive either an oral dose of 50,000 IU vitamin A or placebo. Expanded Programme of Immunisation birth vaccinations were administered after supplementation, with subsequent vaccinations administered at 8, 12 and 16 weeks of age. A range of immunological outcomes were examined up to 17 weeks of age, with additional morbidity and anthropometry follow-up carried out throughout the first year of life. The primary endpoint of this trial is the frequency of circulating T regulatory (Treg) cells expressing gut homing receptors in infants at 17 week post-supplementation, with secondary outcomes including thymus maturation and B cell immune responses.

Discussion: Indicative immunological data from this trial (and its Bangladeshi counterpart), will complement the larger randomised controlled trials (conducted in India, Tanzania and Ghana), on the effectiveness and safety of neonatal vitamin A supplementation in improving infant survival. Combined these trials, in addition to the existing trials, will inform policy.

Trial registration: clinicaltrials.gov NCT01476358.

Figures

Figure 1
Figure 1
Flow chart of the study design. Key: EPI; expanded programme of immunisation; NNVAS; neonatal vitamin A supplementation.

References

    1. WHO. Global prevalence of vitamin A deficiency in populations at risk 1995–2005: WHO global database on vitamin A deficiency. Geneva: World Health Organization; 2009.
    1. Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ. 2011;343:d5094. doi: 10.1136/bmj.d5094.
    1. Fawzi WW, Chalmers TC, Herrera MG, Mosteller F. Vitamin A supplementation and child mortality. A meta-analysis. JAMA. 1993;269(7):898–903. doi: 10.1001/jama.1993.03500070078033.
    1. World Health Organization. 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(9136):1257–1263.
    1. Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, Hidayat S, Tielsch J, West KP Jr, Sommer A. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr. 1996;128(4):489–496. doi: 10.1016/S0022-3476(96)70359-1.
    1. Klemm RD, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J, Sommer A, West KP Jr. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics. 2008;122(1):e242–e250. doi: 10.1542/peds.2007-3448.
    1. Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, John R, Prakash K, Sadanand AV, Edwin N, Kamaraj C. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. BMJ. 2003;327(7409):254. doi: 10.1136/bmj.327.7409.254.
    1. Benn CS, Diness BR, Roth A, Nante E, Fisker AB, Lisse IM, Yazdanbakhsh M, Whittle H, Rodrigues A, Aaby P. Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial. BMJ. 2008;336(7658):1416–1420. doi: 10.1136/.
    1. Malaba LC, Iliff PJ, Nathoo KJ, Marinda E, Moulton LH, Zijenah LS, Zvandasara P, Ward BJ, Humphrey JH. Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. Am J Clin Nutr. 2005;81(2):454–460.
    1. Gogia S, Sachdev HS. Neonatal vitamin A supplementation for prevention of mortality and morbidity in infancy: systematic review of randomised controlled trials. BMJ. 2009;338:b919. doi: 10.1136/bmj.b919.
    1. Bahl R, Bhandari N, Dube B, Edmond K, Fawzi W, Fontaine O, Kaur J, Kirkwood BR, Martines J, Masanja H, Mazumder S, Msham S, Newton S, Oleary M, Ruben J, Shannon C, Smith E, Taneja S, Yoshida S. NEOVITA Study Author Group. Efficacy of early neonatal vitamin A supplementation in reducing mortality during infancy in Ghana, India and Tanzania: study protocol for a randomized controlled trial. Trials. 2012;13:22.
    1. Mora JR, Iwata M, Von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008;8(9):685–698. doi: 10.1038/nri2378.
    1. Mielke LA, Jones SA, Raverdeau M, Higgs R, Stefanska A, Groom JR, Misiak A, Dungan LS, Sutton CE, Streubel G, Bracken AP, Mills KH. Retinoic acid expression associates with enhanced IL-22 production by gammadelta T cells and innate lymphoid cells and attenuation of intestinal inflammation. J Exp Med. 2013;210(6):1117–1124. doi: 10.1084/jem.20121588.
    1. Hall JA, Grainger JR, Spencer SP, Belkaid Y. The role of retinoic acid in tolerance and immunity. Immunity. 2011;35(1):13–22. doi: 10.1016/j.immuni.2011.07.002.
    1. Thurnham DI, Northrop-Clewes CA, McCullough FS, Das BS, Lunn PG. Innate immunity, gut integrity, and vitamin A in Gambian and Indian infants. J Infect Dis. 2000;182(Suppl 1):S23–S28.
    1. Stephensen CB. Vitamin A, infection, and immune function. Annu Rev Nutr. 2001;21:167–192. doi: 10.1146/annurev.nutr.21.1.167.
    1. Pino-Lagos K, Guo Y, Noelle RJ. Retinoic acid: a key player in immunity. Biofactors. 2010;36(6):430–436. doi: 10.1002/biof.117.
    1. Engedal N. Immune regulator vitamin A and T cell death. Vitam Horm. 2011;86:153–178.
    1. Pino-Lagos K, Guo Y, Brown C, Alexander MP, Elgueta R, Bennett KA, De Vries V, Nowak E, Blomhoff R, Sockanathan S, Chandraratna RA, Dmitrovsky E, Noelle RJ. A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity. J Exp Med. 2011;208(9):1767–1775. doi: 10.1084/jem.20102358.
    1. Ross AC. Vitamin A and retinoic acid in T cell-related immunity. Am J Clin Nutr. 2012;96(5):1166S–1172S. doi: 10.3945/ajcn.112.034637.
    1. Stephensen CB, Rasooly R, Jiang X, Ceddia MA, Weaver CT, Chandraratna RA, Bucy RP. Vitamin A enhances in vitro Th2 development via retinoid X receptor pathway. J Immunol. 2002;168(9):4495–4503. doi: 10.4049/jimmunol.168.9.4495.
    1. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med. 2007;204(8):1765–1774. doi: 10.1084/jem.20070719.
    1. Elias KM, Laurence A, Davidson TS, Stephens G, Kanno Y, Shevach EM, O’Shea JJ. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood. 2008;111(3):1013–1020.
    1. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317(5835):256–260. doi: 10.1126/science.1145697.
    1. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. Retinoic acid imprints gut-homing specificity on T cells. Immunity. 2004;21(4):527–538. doi: 10.1016/j.immuni.2004.08.011.
    1. Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CH. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J Immunol. 2007;179(6):3724–3733. doi: 10.4049/jimmunol.179.6.3724.
    1. Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A, Takeuchi H, Ricciardi-Castagnoli P, Rajewsky K, Adams DH, von Andrian UH. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science. 2006;314(5802):1157–1160. doi: 10.1126/science.1132742.
    1. Manicassamy S, Pulendran B. Retinoic acid-dependent regulation of immune responses by dendritic cells and macrophages. Semin Immunol. 2009;21(1):22–27. doi: 10.1016/j.smim.2008.07.007.
    1. DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, Jabri B. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature. 2011;471(7337):220–224. doi: 10.1038/nature09849.
    1. Ross AC, Chen Q, Ma Y. Vitamin A and retinoic acid in the regulation of B-cell development and antibody production. Vitam Horm. 2011;86:103–126.
    1. Diness BR, Fisker AB, Roth A, Yazdanbakhsh M, Sartono E, Whittle H, Nante JE, Lisse IM, Ravn H, Rodrigues A, Aaby P, Benn CS. Effect of high-dose vitamin A supplementation on the immune response to Bacille Calmette-Guerin vaccine. Am J Clin Nutr. 2007;86(4):1152–1159.
    1. Diness BR, Christoffersen D, Pedersen UB, Rodrigues A, Fischer TK, Andersen A, Whittle H, Yazdanbakhsh M, Aaby P, Benn CS. The effect of high-dose vitamin A supplementation given with bacille Calmette-Guerin vaccine at birth on infant rotavirus infection and diarrhea: a randomized prospective study from Guinea-Bissau. J Infect Dis. 2010;202(Suppl):S243–S251.
    1. Diness BR, Martins CL, Bale C, Garly ML, Ravn H, Rodrigues A, Whittle H, Aaby P, Benn CS. The effect of high-dose vitamin A supplementation at birth on measles incidence during the first 12 months of life in boys and girls: an unplanned study within a randomised trial. Br J Nutr. 2011;1:4.
    1. United Nations. UN Data Country Profile - Gambia. 2014. 2014-Jan-27.
    1. UNICEF. At a Glance: Gambia - Statistics. 2013. 2014-Jan-27.
    1. Bah A, Semega-Janneh I, Prentice AM, Bates C. Nationwide survey on the prevalence of vitamin A and iron deficiency in women and children in The Gambia. National Nutrition Agency and Medical Research Council. 2001. pp. 1–56.
    1. Darboe MK, Thurnham DI, Morgan G, Adegbola RA, Secka O, Solon JA, Jackson SJ, Northrop-Clewes C, Fulford TJ, Doherty CP, Prentice AM. Effectiveness of an early supplementation scheme of high-dose vitamin A versus standard WHO protocol in Gambian mothers and infants: a randomised controlled trial. Lancet. 2007;369(9579):2088–2096. doi: 10.1016/S0140-6736(07)60981-7.
    1. Tanumihardjo SA, Cheng JC, Permaesih D, Muherdiyantiningsih, Rustan E, Muhilal, Karyadi D, Olson JA. Refinement of the modified-relative-dose–response test as a method for assessing vitamin A status in a field setting: experience with Indonesian children. Am J Clin Nutr. 1996;64(6):966–971.
    1. Hasselbalch H, Nielsen MB, Jeppesen D, Pedersen JF, Karkov J. Sonographic measurement of the thymus in infants. Eur Radiol. 1996;6(5):700–703.
    1. Ribeiro RM, Perelson AS. Determining thymic output quantitatively: using models to interpret experimental T-cell receptor excision circle (TREC) data. Immunol Rev. 2007;216:21–34.
    1. Burl S, Adetifa UJ, Cox M, Touray E, Ota MO, Marchant A, Whittle H, McShane H, Rowland-Jones SL, Flanagan KL. Delaying bacillus Calmette-Guerin vaccination from birth to 4 1/2 months of age reduces postvaccination Th1 and IL-17 responses but leads to comparable mycobacterial responses at 9 months of age. J Immunol. 2010;185(4):2620–2628. doi: 10.4049/jimmunol.1000552.
    1. West KP Jr, Katz J, Shrestha SR, LeClerq SC, Khatry SK, Pradhan EK, Adhikari R, Wu LS, Pokhrel RP, Sommer A. Mortality of infants < 6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am J Clin Nutr. 1995;62(1):143–148.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere