B. Infantis Supplementation to Improve Immunity in Infants Exposed to HIV

Study Overview
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Brief Summary
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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

Detailed Description
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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.

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

Conditions
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Hiv, Vaccine Reaction, Microbial Colonization, Infant Development

Intervention / Treatment
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* Dietary Supplement: B. infantis Rosell®-33
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: B. infantis Rosell®-33<br>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<br>* B. infantis Rosell®-33 + maltodextrin<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo (containing all materials besides B. infantis Rosell®-33) for 28 days from day 1-3 of life. | Dietary Supplement: Placebo<br>* Maltodextrin<br>|

What is the study measuring?
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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 | 
| Markers of intestinal inflammation and microbial translocation | 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 | 
| 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 | 

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 |