B. Infantis Supplementation to Improve Immunity in Infants Exposed to HIV (BifIID)

Bifidobacterium Infantis Supplementation in Early Life to Improve Immunity in Infants Exposed to HIV: a Randomized, Placebo-controlled, Double-blind Trial

The primary objectives of this study are to evaluate the effect of early-life B. infantis Rosell®-33 supplementation in infants exposed to HIV on:

• gut microbiome composition and diversity at 4 weeks of life
• markers of intestinal inflammation and microbial translocation at 4 weeks of life
• Th1 cytokine responses to BCG at 7 weeks and 36 weeks of life

The secondary objectives include to evaluate the effect of B. infantis Rosell®-33 supplementation on:

• longitudinal succession of the gut microbiota composition, diversity and function
• relative and absolute abundance of B. infantis in infant stool during the first 36 weeks of life
• stool metabolome
• T cell subset ontogeny during the first 9 months of life.

Exploratory objectives are to evaluate whether B. infantis Rosell®-33 supplementation improves:

• infant growth
• all-cause morbidity
• neurodevelopment during the first 9 months of life
• antibody responses to early childhood vaccines

Study Overview

• Status: Recruiting
• Conditions: Vaccine Reaction; Hiv; Microbial Colonization; Infant Development
• Intervention / Treatment: Dietary supplement: Placebo; Dietary supplement: B. infantis Rosell®-33

Detailed Description

Infants who are born to mothers with 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 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, a randomized trial of B. infantis Rosell®-33 versus placebo given during the first month of life in South African iHEU will be conducted.

This is a parallel, randomised, controlled study. 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 x109 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.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Heather Jaspan, MD PHD; Phone Number: 2068543336; Email: hbjaspan@gmail.com
• Study Contact Backup: Name: Anna-Ursula Happel, PhD; Phone Number: + 27 21 406 6823; Email: anna.happel@uct.ac.za

Study Locations

• South Africa
  • Cape Town, South Africa
    • Recruiting
    • Khayelitsha Site B Midwife Obstetric Unit
    • Contact: Busi Tyhenge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria Mother:

• Willing and able to provide signed and dated informed consent form
• 18 years of age or older
• Documented HIV seropositive
• Antiretroviral therapy initiated before the third trimester of pregnancy
• Planning on exclusively breastfeeding the infant for the first 6 months of life

Inclusion Criteria Infant:

• Documented HIV seronegative at birth
• Born at term (completed at least 37 weeks of gestation)
• Birth weight >2.4kgs

Exclusion Criteria:

• Severe illnesses, e.g. Sepsis
• current TB or known household TB contact
• Chronic disorder or medications (other than antiretrovirals and cotrimoxazole prophylaxis) that in the opinion of the investigator would alter immunity
• Pregnancy or delivery complications including birth asphyxia, seizures, sepsis, major congenital anomalies or congenital infections
• Known contraindications to components of the interventional products
• Taking additional probiotics or prebiotics
• Any condition that in the opinion of the investigator would make participation in the trial unsafe

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: B. infantis Rosell®-33; Participants will receive 8 x 109 CFU B. infantis Rosell®-33 per dose (single microbial active ingredient) and carrier material (maltodextrin) for 28 days from day 1-3 of life.	Dietary supplement: B. infantis Rosell®-33; B. infantis Rosell®-33 + maltodextrin
Placebo Comparator: Placebo; Participants will receive placebo (containing all materials besides B. infantis Rosell®-33) for 28 days from day 1-3 of life.	Dietary supplement: Placebo; Maltodextrin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gut microbiome	Alpha (Shannon) and Beta (Bray Curtis and UniFrac) diversity metrics on the entire microbial communities, assessed by bacterial shotgun metagenomics of infant stool, will be compared between treatment arms	4 weeks of age
BCG vaccine respone	Frequencies of total net cytokine producing cells in response to stimulation with BCG will be compared between arms.	7 weeks of age
BCG vaccine respone	Frequencies of total net cytokine producing cells in response to stimulation with BCG will be compared between arms.	36 weeks of age
Markers of intestinal inflammation and microbial translocation	Concentration of markers of intestinal inflammation and microbial translocation (Lipocalin-2 (Lcn-2), sCD163, I-FABP and LBP measured by ELISA in infant plasma) will be compared cross-sectionally at each time point between groups using Mann-Whitney U tests	4 - 36 weeks of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Longitudinal succession in gut microbiota composition, diversity and function	Longitudinal multi-omic variation will be visualized using PCoA and tSNE plots, and cross-sectional differences in multi-omic profiles will be assessed using PERMANOVAs.	4 - 36 weeks of age
Stool metabolome	For cross-sectional metabolite differential abundance analyses, we will use generalized linear regression (continuous dependent variable) and logistic regression (Boolean dependent variable) with an FDR correction.	4 weeks of age
T cell subsets frequencies	T cell subsets frequencies will be compared cross-sectionally between groups	4 - 36 weeks of age

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of total B. infantis and B. infantis Rosell®-33 in stool	qPCR will be used to assess whether B. infantis Rosell®-33 colonized.	4 - 36 weeks of age
Infant growth	Infant anthropometry will be recorded at each visit to calculate infant length for age (LAZ), weight for age (WAZ) and weight for length (WLZ) Z scores and will be compared between the two arms.	4 - 36 weeks of age
All-cause infectious morbidity	Infectious morbidity data will be quantify and compare occurrence of infectious morbidity outcomes between randomisation arms.	4 - 36 weeks of age
Vaccine antibody titres	Antibody titres to early childhood vaccines will be assessed and compared by treatment arm.	4 - 36 weeks of age
Infant neurodevelopment milestones	Comprehensive neurodevelopment assessment will be conducted, e.g. using the Bayley Scales of Infant and Toddler Development, 3rd edition, or similar assessment tools, and developmental scores compared between the two arms, as well as the proportion of infants passing each developmental area assessed. Higher scores indicate better outcomes.	24 and 36 weeks of age

Collaborators and Investigators

• Sponsor: University of Cape Town
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); University of Washington; Seattle Children's Hospital; University of Stellenbosch; Institute for Systems Biology
• Investigators: Principal Investigator: Heather Jaspan, MD PHD, Seattle Children's Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: June 19, 2023
• First Submitted That Met QC Criteria: June 19, 2023
• First Posted (Actual): June 28, 2023

Study Record Updates

• Last Update Posted (Actual): August 22, 2024
• Last Update Submitted That Met QC Criteria: August 20, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases
• Other Study ID Numbers: 697/2022; R01HD109089 (U.S. NIH Grant/Contract); PACTR202301748714019 (Registry Identifier: Pan African Clinical Trials Registry)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No