Top

BMC Complementary Medicine and Therapies

Published in:

Open Access 01-12-2023 | Human Immunodeficiency Virus | Study Protocol

Bifidobacterium infantis supplementation versus placebo in early life to improve immunity in infants exposed to HIV: a protocol for a randomized trial

Authors: Anna-Ursula Happel, Lerato Rametse, Brandon Perumaul, Christian Diener, Sean M. Gibbons, Donald D. Nyangahu, Kirsten A. Donald, Clive Gray, Heather B. Jaspan

Published in: BMC Complementary Medicine and Therapies | Issue 1/2023

Abstract

Introduction

Infants who are born from mothers with HIV (infants who are HIV exposed but uninfected; iHEU) are at higher risk of morbidity and display multiple immune alterations compared to infants who are HIV-unexposed (iHU). Easily implementable strategies to improve immunity of iHEU, and possibly subsequent clinical health outcomes, are needed. iHEU have altered gut microbiome composition and bifidobacterial depletion, and relative abundance of Bifidobacterium infantis has been associated with immune ontogeny, including humoral and cellular vaccine responses. Therefore, we will assess microbiological and immunological phenotypes and clinical outcomes in a randomized, double-blinded trial of B. infantis Rosell®-33 versus placebo given during the first month of life in South African iHEU.

Methods

This is a parallel, randomised, controlled trial. Two-hundred breastfed iHEU will be enrolled from the Khayelitsha Site B Midwife Obstetric Unit in Cape Town, South Africa and 1:1 randomised to receive 8 × 10⁹ CFU B. infantis Rosell®-33 daily or placebo for the first 4 weeks of life, starting on day 1–3 of life. Infants will be followed over 36 weeks with extensive collection of meta-data and samples. Primary outcomes include gut microbiome composition and diversity, intestinal inflammation and microbial translocation and cellular vaccine responses. Additional outcomes include biological (e.g. gut metabolome and T cell phenotypes) and clinical (e.g. growth and morbidity) outcome measures.

Discussion

The results of this trial will provide evidence whether B. infantis supplementation during early life could improve health outcomes for iHEU.

Ethics and dissemination

Approval for this study has been obtained from the ethics committees at the University of Cape Town (HREC Ref 697/2022) and Seattle Children’s Research Institute (STUDY00003679).

Trial registration

Pan African Clinical Trials Registry Identifier: PACTR202301748714019. Clinical.trials.gov: NCT05923333.

Protocol Version: Version 1.8, dated 18 July 2023.

Chi BH, Stringer JSA, Moodley D. Antiretroviral drug regimens to prevent mother-to-child transmission of HIV: a review of scientific, program, and policy advances for Sub-Saharan Africa. Curr HIV/AIDS Rep. 2013;10(2):124–33. https://doi.org/10.1007/s11904-013-0154-z.CrossRefPubMedPubMedCentral

Slogrove AL, Esser MM, Cotton MF, et al. A Prospective Cohort Study of Common Childhood Infections in South African HIV-exposed Uninfected and HIV-unexposed Infants. Pediatr Infect Dis J. 2017;36(2). https://journals.lww.com/pidj/Fulltext/2017/02000/A_Prospective_Cohort_Study_of_Common_Childhood.14.aspx.

Kuhn L, Kasonde P, Sinkala M, et al. Does severity of HIV disease in HIV-infected mothers affect mortality and morbidity among their uninfected infants? Clin Infect Dis. 2005;41(11):1654–61. https://doi.org/10.1086/498029.CrossRefPubMed

Epalza C, Goetghebuer T, Hainaut M, et al. High Incidence of Invasive Group B Streptococcal Infections in HIV-Exposed Uninfected Infants. Pediatrics. 2010;126(3):e631–8. https://doi.org/10.1542/peds.2010-0183.CrossRefPubMed

Kidzeru EB, Hesseling AC, Passmore JAS, et al. In-utero exposure to maternal HIV infection alters T-cell immune responses to vaccination in HIV-uninfected infants. AIDS. 2014;28(10):1421–30. https://doi.org/10.1097/QAD.0000000000000292.CrossRefPubMed

Dirajlal-Fargo S, Mussi-Pinhata MM, Weinberg A, et al. HIV-exposed-uninfected infants have increased inflammation and monocyte activation. AIDS. 2019;33(5):845–53. https://doi.org/10.1097/QAD.0000000000002128.CrossRefPubMed

Jones CE, Naidoo S, De Beer C, Esser M, Kampmann B, Hesseling AC. Maternal HIV infection and antibody responses against vaccine-preventable diseases in uninfected infants. JAMA. 2011;305(6):576–84. https://doi.org/10.1001/jama.2011.100.CrossRefPubMed

Mazzola TN, da Silva MTN, Abramczuk BM, et al. Impaired Bacillus Calmette-Guérin cellular immune response in HIV-exposed, uninfected infants. AIDS. 2011;25(17):2079–87. https://doi.org/10.1097/QAD.0b013e32834bba0a.CrossRefPubMed

Sanz-Ramos M, Manno D, Kapambwe M, et al. Reduced Poliovirus vaccine neutralising-antibody titres in infants with maternal HIV-exposure. Vaccine. 2013;31(16):2042–9. https://doi.org/10.1016/j.vaccine.2013.02.044.CrossRefPubMed

10.

Lohman-Payne B, Gabriel B, Park S, et al. HIV-exposed uninfected infants: elevated cord blood Interleukin 8 (IL-8) is significantly associated with maternal HIV infection and systemic IL-8 in a Kenyan cohort. Clin Transl Med. 2018;7(1):26. https://doi.org/10.1186/s40169-018-0206-5.CrossRefPubMedPubMedCentral

11.

Nyemba DC, Kalk E, Madlala HP, et al. Lower birth weight-for-age and length-for-age z-scores in infants with in-utero HIV and ART exposure: a prospective study in Cape Town, South Africa. BMC Pregnancy Childbirth. 2021;21(1):354. https://doi.org/10.1186/s12884-021-03836-z.CrossRefPubMedPubMedCentral

12.

Aizire J, Sikorskii A, Ogwang LW, et al. Decreased growth among antiretroviral drug and HIV-exposed uninfected versus unexposed children in Malawi and Uganda. AIDS. 2020;34(2). https://journals.lww.com/aidsonline/Fulltext/2020/02010/Decreased_growth_among_antiretroviral_drug_and.7.aspx.

13.

le Roux SM, Donald KA, Brittain K, et al. Neurodevelopment of breastfed HIV-exposed uninfected and HIV-unexposed children in South Africa. AIDS. 2018;32(13):1781–91. https://doi.org/10.1097/QAD.0000000000001872.CrossRefPubMed

14.

McHenry MS, McAteer CI, Oyungu E, et al. Neurodevelopment in Young Children Born to HIV-Infected Mothers: a Meta-analysis. Pediatrics. 2018;141(2). https://doi.org/10.1542/peds.2017-2888.

15.

Slogrove A, Powis K, Johnson L, Stover J, Mahy M. Estimates of the global population of children who are HIV-exposed and uninfected, 2000–18: a modelling study. Lancet Glob Health. 2019;8. https://doi.org/10.1016/S2214-109X(19)30448-6.

16.

Sanidad KZ, Zeng MY. Neonatal gut microbiome and immunity. Curr Opin Microbiol. 2020;56:30–7. https://doi.org/10.1016/j.mib.2020.05.011.CrossRefPubMedPubMedCentral

17.

Gensollen T, Iyer SS, Kasper DL, Blumberg RS. How colonization by microbiota in early life shapes the immune system. Science. 2016;352(6285):539–44. https://doi.org/10.1126/science.aad9378.CrossRefPubMedPubMedCentral

18.

Turroni F, Milani C, Duranti S, et al. Bifidobacteria and the infant gut: an example of co-evolution and natural selection. Cell Mol Life Sci. 2018;75(1):103–18. https://doi.org/10.1007/s00018-017-2672-0.CrossRefPubMed

19.

Terrazzan Nutricionist AC, Procianoy RS, Roesch LFW, Corso AL, Dobbler PT, Silveira RC. Meconium microbiome and its relation to neonatal growth and head circumference catch-up in preterm infants. PLoS One. 2020;15(9):e0238632.CrossRefPubMedPubMedCentral

20.

He Q, Kwok LY, Xi X, et al. The meconium microbiota shares more features with the amniotic fluid microbiota than the maternal fecal and vaginal microbiota. Gut Microbes. 2020;12(1):1794266. https://doi.org/10.1080/19490976.2020.1794266.CrossRefPubMedPubMedCentral

21.

Bender JM, Li F, Martelly S, et al. Maternal HIV infection influences the microbiome of HIV-uninfected infants. Sci Transl Med. 2016;8(349):349ra100-349ra100. https://doi.org/10.1126/scitranslmed.aaf5103.CrossRefPubMedPubMedCentral

22.

Machiavelli A, Duarte RTD, de Pires MMS, Zárate-Bladés CR, Pinto AR. The impact of in utero HIV exposure on gut microbiota, inflammation, and microbial translocation. Gut Microbes. 2019;10(5):599–614. https://doi.org/10.1080/19490976.2018.1560768.CrossRefPubMedPubMedCentral

23.

Grant-Beurmann S, Jumare J, Ndembi N, et al. Dynamics of the infant gut microbiota in the first 18 months of life: the impact of maternal HIV infection and breastfeeding. Microbiome. 2022;10(1):61. https://doi.org/10.1186/s40168-022-01230-1.CrossRefPubMedPubMedCentral

24.

Jc L, Fd N, Rc E, et al. Evolution of the gut microbiome in HIV-exposed uninfected and unexposed infants during the first year of life. mBio. 2022;13(5):e01229-22. https://doi.org/10.1128/mbio.01229-22.CrossRef

25.

Wang Z, Usyk M, Sollecito CC, et al. Altered Gut Microbiota and Host Metabolite Profiles in Women With Human Immunodeficiency Virus. Clin Infect Dis. 2020;71(9):2345–53. https://doi.org/10.1093/cid/ciz1117.CrossRefPubMed

26.

Nyangahu DD, Lennard KS, Brown BP, et al. Disruption of maternal gut microbiota during gestation alters offspring microbiota and immunity. Microbiome. 2018;6(1):124. https://doi.org/10.1186/s40168-018-0511-7.CrossRefPubMedPubMedCentral

27.

Gonzalez-Perez G, Hicks AL, Tekieli TM, Radens CM, Williams BL, Lamousé-Smith ESN. Maternal Antibiotic Treatment Impacts Development of the Neonatal Intestinal Microbiome and Antiviral Immunity. J Immunol. 2016;196(9):3768–79. https://doi.org/10.4049/jimmunol.1502322.CrossRefPubMed

28.

Nyangahu DD, Jaspan HB. Influence of maternal microbiota during pregnancy on infant immunity. Clin Exp Immunol. 2019;198(1):47–56. https://doi.org/10.1111/cei.13331.CrossRefPubMedPubMedCentral

29.

Harris V, Ali A, Fuentes S, et al. Rotavirus vaccine response correlates with the infant gut microbiota composition in Pakistan. Gut Microbes. 2018;9(2):93–101. https://doi.org/10.1080/19490976.2017.1376162.CrossRefPubMed

30.

Parker EPK, Praharaj I, Zekavati A, et al. Influence of the intestinal microbiota on the immunogenicity of oral rotavirus vaccine given to infants in south India. Vaccine. 2018;36(2):264–72. https://doi.org/10.1016/j.vaccine.2017.11.031.CrossRefPubMedPubMedCentral

31.

Praharaj I, Parker EPK, Giri S, et al. Influence of Nonpolio Enteroviruses and the bacterial gut microbiota on oral poliovirus vaccine response: a study from South India. J Infect Dis. 2019;219(8):1178–86. https://doi.org/10.1093/infdis/jiy568.CrossRefPubMed

32.

Huda MN, Ahmad SM, Alam MJ, et al. Bifidobacterium abundance in early infancy and vaccine response at 2 years of age. Pediatrics. 2019;143(2):e20181489. https://doi.org/10.1542/peds.2018-1489.CrossRefPubMed

33.

Huda MN, Lewis Z, Kalanetra KM, et al. Stool microbiota and vaccine responses of infants. Pediatrics. 2014;134(2):e362–72. https://doi.org/10.1542/peds.2013-3937.CrossRefPubMedPubMedCentral

34.

Pabst H, Grace M, Godel J, Cho H, Spady D. Effect of breast-feeding on immune response to bcg vaccination. Lancet. 1989;333(8633):295–7. https://doi.org/10.1016/S0140-6736(89)91307-X.CrossRef

35.

Bin-Nun A, Bromiker R, Wilschanski M, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr. 2005;147:192–6.CrossRefPubMed

36.

Lin HC, Su BH, Chen AC, et al. Oral Probiotics Reduce the Incidence and Severity of Necrotizing Enterocolitis in Very Low Birth Weight Infants. Pediatrics. 2005;115(1):1–4. https://doi.org/10.1542/peds.2004-1463.CrossRefPubMed

37.

Escribano J, Ferré N, Gispert-Llaurado M, et al. Bifidobacterium longum subsp infantis CECT7210-supplemented formula reduces diarrhea in healthy infants: a randomized controlled trial. Pediatr Res. 2018;83(6):1120–8. https://doi.org/10.1038/pr.2018.34.CrossRefPubMed

38.

Nguyen M, Holdbrooks H, Mishra P, et al. Impact of Probiotic B. infantis EVC001 Feeding in Premature Infants on the Gut Microbiome, Nosocomially Acquired Antibiotic Resistance, and Enteric Inflammation . Front Pediatr. 2021;9:24. https://www.frontiersin.org/article/10.3389/fped.2021.618009.

39.

Henrick BM, Chew S, Casaburi G, et al. Colonization by B. infantis EVC001 modulates enteric inflammation in exclusively breastfed infants. Pediatr Res. 2019;86(6):749–57. https://doi.org/10.1038/s41390-019-0533-2.CrossRefPubMedPubMedCentral

40.

Groeger D, O’Mahony L, Murphy EF, et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes. 2013;4(4):325–39. https://doi.org/10.4161/gmic.25487.CrossRefPubMedPubMedCentral

41.

Henrick BM, Rodriguez L, Lakshmikanth T, et al. Bifidobacteria-mediated immune system imprinting early in life. Cell. 2021;184(15):3884-3898.e11. https://doi.org/10.1016/j.cell.2021.05.030.CrossRefPubMed

42.

Gu J, Ni X, Pan X, et al. Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions. Cell Mol Immunol. 2017;14(6):521–8. https://doi.org/10.1038/cmi.2016.30.CrossRefPubMed

43.

O’Brien CE, Meier AK, Cernioglo K, et al. Early probiotic supplementation with B. infantis in breastfed infants leads to persistent colonization at 1 year. Pediatr Res. Published online 2021. https://doi.org/10.1038/s41390-020-01350-0.

44.

D’Souza AW, Moodley-Govender E, Berla B, et al. Cotrimoxazole Prophylaxis Increases Resistance Gene Prevalence and α-Diversity but Decreases β-Diversity in the Gut Microbiome of Human Immunodeficiency Virus-Exposed, Uninfected Infants. Clin Infect Dis. 2020;71(11):2858–68. https://doi.org/10.1093/cid/ciz1186.CrossRefPubMed

45.

De Andrés J, Manzano S, García C, Rodríguez JM, Espinosa-Martos I, Jiménez E. Modulatory effect of three probiotic strains on infants’ gut microbial composition and immunological parameters on a placebo-controlled, double-blind, randomised study. Benef Microbes. 2018;9(4):573–84. https://doi.org/10.3920/BM2017.0132.CrossRefPubMed

46.

Manzano S, De Andrés J, Castro I, Rodríguez JM, Jiménez E, Espinosa-Martos I. Safety and tolerance of three probiotic strains in healthy infants: a multi-centre randomized, double-blind, placebo-controlled trial. Benef Microbes. 2017;8(4):569–78. https://doi.org/10.3920/BM2017.0009.CrossRefPubMed

47.

Xiao L, Gong C, Ding Y, et al. Probiotics maintain intestinal secretory immunoglobulin A levels in healthy formula-fed infants: a randomised, double-blind, placebo-controlled study. Benef Microbes. 2019;10(7):729–39. https://doi.org/10.3920/BM2019.0025.CrossRefPubMed

48.

Tremblay A, Xu X, Colee J, Tompkins TA. Efficacy of a Multi-Strain Probiotic Formulation in Pediatric Populations: A Comprehensive Review of Clinical Studies. Nutrients. 2021;13(6). https://doi.org/10.3390/nu13061908

49.

Tchakoute CT, Sainani KL, Osawe S, et al. Breastfeeding mitigates the effects of maternal HIV on infant infectious morbidity in the Option B+ era. AIDS. 2018;32(16):2383–91. https://doi.org/10.1097/QAD.0000000000001974.CrossRefPubMed

50.

Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. https://doi.org/10.1186/s13059-014-0550-8.CrossRefPubMedPubMedCentral

51.

Martin BD, Witten D, Willis AD. Modeling microbial abundances and dysbiosis with beta-binomial regression. Ann Appl Stat. 2020;14(1):94–115. https://doi.org/10.1214/19-AOAS1283.CrossRefPubMedPubMedCentral

52.

Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc Ser B (Methodol). 1995;57(1):289–300. https://doi.org/10.1111/j.2517-6161.1995.tb02031.x.CrossRef

53.

Lin L, Finak G, Ushey K, et al. COMPASS identifies T-cell subsets correlated with clinical outcomes. Nat Biotechnol. 2015;33(6):610–6. https://doi.org/10.1038/nbt.3187.CrossRefPubMedPubMedCentral

54.

Van der Maaten L, Hinton G. Visualizing data using t-SNE. J Mach Learn Res. 2008;9(11):2579–605.

55.

Christian D, Gibbons SM, Osbaldo RA. MICOM: Metagenome-Scale Modeling To Infer Metabolic Interactions in the Gut Microbiota. mSystems. 2020;5(1):e00606-19. https://doi.org/10.1128/mSystems.00606-19.CrossRef

56.

Oksanen J, Blanchet GF, Friendly M, et al. vegan: Community Ecology Package. Published online 2019.

57.

Quintelier K, Couckuyt A, Emmaneel A, Aerts J, Saeys Y, Van Gassen S. Analyzing high-dimensional cytometry data using FlowSOM. Nat Protoc. 2021;16(8):3775–801. https://doi.org/10.1038/s41596-021-00550-0.CrossRefPubMed

58.

Villar J, Cheikh Ismail L, Victora CG, et al. International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet. 2014;384(9946):857–68. https://doi.org/10.1016/S0140-6736(14)60932-6.CrossRefPubMed

59.

U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. Published 2017. https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. Accessed 18 Apr 2023.

Title: Bifidobacterium infantis supplementation versus placebo in early life to improve immunity in infants exposed to HIV: a protocol for a randomized trial
Authors: Anna-Ursula Happel
Lerato Rametse
Brandon Perumaul
Christian Diener
Sean M. Gibbons
Donald D. Nyangahu
Kirsten A. Donald
Clive Gray
Heather B. Jaspan
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Human Immunodeficiency Virus
Published in: BMC Complementary Medicine and Therapies / Issue 1/2023
Electronic ISSN: 2662-7671
DOI: https://doi.org/10.1186/s12906-023-04208-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Bifidobacterium infantis supplementation versus placebo in early life to improve immunity in infants exposed to HIV: a protocol for a randomized trial

Abstract

Introduction

Methods

Discussion

Ethics and dissemination

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Discussion

Ethics and dissemination

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2023

Reasons for using traditional and complementary care by people living with HIV on antiretroviral therapy and association with interrupted care: a mixed methods study in Eswatini

Gut microbiota combined with fecal metabolomics reveals the effects of FuFang Runzaoling on the microbial and metabolic profiles in NOD mouse model of Sjögren’s syndrome

Safety profile of colocasia esculenta tuber extracts in benign prostate hyperplasia

Adapting an evidence-based mindfulness-based intervention for sheltered youth experiencing homelessness

Effects of garlic supplementation on components of metabolic syndrome: a systematic review, meta-analysis, and meta-regression of randomized controlled trials

Trends and quality of randomized controlled trials on acupuncture conducted in Japan by decade from the 1960s to the 2010s: a systematic review