Overview

Burden: Environmental Enteric Dysfunction (EED) is an enteropathic condition characterised by altered gut permeability, infiltration of immune cells, and changes in villous architecture and cell differentiation. EED is a major reason of malnourishment, poor neurological development, stunting, oral vaccine failure, and infection. It is believed that EED is responsible for 40% of all childhood stunting.

Relevance: This trial aims to investigate the concept that a probiotic or live biotherapeutic product, capable of improving gut microbiota composition, can also displace enteropathogens and reduce biomarkers of intestinal inflammation, thereby promoting gut health. This will restore healthy microbial signalling to the host epithelium, ameliorate barrier function through secretion of mucus and antimicrobial factors, and improve nutrient availability.

Objectives: The primary objective is to assess if administration of oral vancomycin followed by VE818 to pregnant women colonised with at least 2 out of 11 selected bacterial enteropathogens results in a significant change in the mean count of these organisms between the baseline and 2 weeks after completion of the intervention (Study Day 35d +2), compared to oral vancomycin followed by placebo.

Methods: Pregnant women will be recruited from the community of Matiari in Pakistan. The study population will be women aged 18 years or older in the first trimester or early second trimester of pregnancy. Study procedures will be explained in detail, and written consent will be taken before enrollment. Those women who give consent to participation will undergo a screening process, which will check if any exclusion criteria are fulfilled. After consent and screening, they will be randomised into one of the three arms: intervention arm (oral vancomycin followed by VE818), placebo-control arm (oral vancomycin followed by placebo), or observation-only arm. The allocation sequence will be generated by the trial statistician using a code with block permutation. The participant will remain free to withdraw at any time from the trial without giving reasons and without prejudicing her further treatment. Biological samples, including blood, saliva, urine, stool, vaginal swab, and intestinal luminal contents through CapScan. CapScan is a non-invasive device (capsule) that collects gastrointestinal samples along the gastrointestinal tract following ingestion and passes into the stool.

Outcome measures/variables: The primary endpoint is the change in the mean count in the number of 11 selected fecal bacterial pathogen groups present between baseline and 2 weeks after completion of the 14-day course with Placebo or VE818 (Study arms 2 and 3), which corresponds to the 35th day, +2 from the first dose of oral vancomycin.

The 11 enteropathogen targets will be detected by customized real-time quantitative PCR-based TaqMan Array Cards (TAC-qPCR) and include the following organisms: Aeromonas, Campylobacter coli, Campylobacter jejuni, Campylobacter Pan, Enteroaggregative Escherichia coli (E. coli), Enteropathogenic E. coli, Enterotoxigenic E. coli, Plesiomonas, Shigella_Enteroinvasive E. coli (EIEC), Salmonella, and Klebsiella pneumoniae

Eligibility

Inclusion criteria

• Women aged 18 years or older in their first or early second trimester of pregnancy (13-17 weeks of gestational age [GA]), living in defined geographical areas of Bangladesh (Matlab), Pakistan, Zambia, and Burkina Faso, where it can be assumed that environmental enteropathy is prevalent
• Presence of any 2 out of 11 selected bacterial pathogen targets (Aeromonas, Campylobacter coli, Campylobacter jejuni, Campylobacter Pan, Enteroaggregative Escherichia coli, Enteropathogenic Escherichia coli, Enterotoxigenic Escherichia coli, Plesiomonas, Shigella_EIEC, Salmonella and Klebsiella pneumoniae in fecal samples measured by TAC-qPCR.
• Presence of any of the following WASH conditions -
  1. use surface water, unimproved water, or limited water for drinking; OR
  2. use surface water, unimproved water, or limited water for cooking; OR
  3. use surface water, unimproved water, or limited water for washing utensils; OR
  4. practice open defecation, use unimproved sanitation (toilet facility), or limited sanitation (toilet facility); OR
  5. lack facility or have limited facility for handwashing

Exclusion criteria

Potential participants will not be enrolled if they:

• have MUAC ≥30 cm
• are carrying more than one fetus (i.e., multiple pregnancy)
• have diarrhea, defined as the passage of three or more loose stools per 24 hours, or have had diarrhea in the preceding 14 days
• have fever or an active infection
• have taken antibiotics or probiotics in the preceding 14 days
• have taken steroids or non-steroidal anti-inflammatory drugs in the preceding 14 days
• have severe anemia as determined using finger stick Hb < 8 g/dl
• have a history of chronic digestive disease
• have any gastrointestinal contraindication to ingestion of a capsule (known or suspected gastrointestinal obstruction, stricture, fistula, gastroparesis, or any swallowing disorder)
• have known immunocompromised status (known history of HIV infection, autoimmune disease, diabetes mellitus, etc.)
• have known drug hypersensitivity/allergy/intolerance
• have chronic disease or any other illness or condition which in the opinion of the investigator will complicate the assessment of safety or efficacy
• are medically disqualified: Any potential participant who is deemed medically unfit for trial enrollment by a non-study healthcare provider, due to the presence of severe or unstable health conditions that could compromise safety or interfere with the study outcomes, will be excluded from participation
• have a plan to observe fast any time during the intervention period
• have a plan to leave the study area within the follow-up period
• are participating in any other interventional trial
• belong to a household from which another woman is already enrolled in the study
• but may be enrolled if/when these disqualifiers have expired.