Project summary

Diarrhea is one of the main causes of child deaths globally, killing nearly two million every year. One of the most important causes is the rotavirus. National immunizations have reduced rotavirus-related diarrhea, but vaccine efficacy in Africa remains suboptimal (30-60%) compared to developed nations (80-90%). The efficacy difference could be attributed to various factors, including composition of gut microbiota.  

In low-income countries the intestinal microbiota of children may undergo significant alterations due to several factors, including exposure to faecal contaminated environments, infections caused by pathogens, frequent administration of antibiotics, and malnutrition. Furthermore, the occurrence of environmental enteropathy, which arises from repeated exposure to pathogens, is common. Healthy gut bacteria composition may prevent colonisation by pathogenic bacteria, protecting against gut damage, and may also stimulate gut immune responses. 

Use of supplementary probiotics –live non-pathogenic bacterial cultures are considered as an innovative strategy which might be able to temporarily shift the gut microbiota and boost immune responses when given alongside rotavirus vaccines. However, there is limited data. 

PRoRota project aims to assess the efficacy and safety of using probiotics together with routine rotavirus vaccines and enhanced WASH education (Water, Sanitation and Hygiene) in reducing diarrheal diseases in infants. Specifically the project aims:  

1. To determine the immunogenicity of the rotavirus vaccine among infants receiving probiotic treatment compared to placebo.  

2. To evaluate the effect of probiotic supplementation on gut colonization by multi-drug-resistant bacteria, specifically extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E), and on the asymptomatic carriage of diarrhoeagenic pathogens in infants. Additionally, to determine if this reduction in bacterial colonization translates to a significant decrease in antibiotic consumption. 

3. To evaluate the cost and cost-effectiveness of using probiotics as an adjunct therapy in preventing childhood diarrhea and antimicrobial resistance versus the standard of care. 

4. To assess the acceptability and feasibility of using probiotics in infants among key stakeholders.  
5. To integrate historical meteorological data with prospective study site data to model the relationship between climate variables and diarrheal disease’s incidence, informing the development of predictive early warning systems.  

This will be a pragmatic, two-arm, double-blind, placebo-controlled, multi-country, individually randomized trial.

4000 healthy newborns between 0-3 days of age will be recruited and followed up to 6 months of age. Newborns will receive either a daily multi-strain probiotic supplement or placebo for four weeks. This will be followed by booster doses every four weeks up to 16 weeks of age. The intervention will be administered alongside the standard rotavirus vaccination schedule and enhanced WASH education. 

The randomized clinical trial will be an adaptive design where the total sample size of the study will be reassessed according to interim analysis data on the primary outcome, i.e. cumulative incidence of all-cause diarrhea and the effect size of the intervention.  

Study will collect dried blood spot and saliva samples for analysis of immune response to the vaccine, and stool samples for gut microbiome and diarrhea pathogen analyses.

1. We hypothesize that probiotic supplementation from birth to 14 weeks (with a primary month and boosters at 6, 10, and 14 weeks) will significantly stabilize the gut microbiome and reduce the incidence of all-cause diarrhea by 6 months compared to the standard of care;
2. That the concurrent administration of probiotics with routine childhood vaccinations is a cost-effective intervention that will improve rotavirus vaccine immunogenicity in infants compared to the standard of care;
3. That the probiotic regimen will significantly:
   • reduce the incidence of gut colonization by extended-spectrum beta-lactamase-producing (ESBL) bacteria, and
   • lower antibiotic consumption in infants compared to controls;
4. That machine learning models integrating climatic variables will accurately forecast diarrheal disease incidence, providing effective early warning signals to guide the strategic deployment of probiotics and vaccinations.