Feasibility, Safety, and Impact of the Probiotics Lactiplantibacillus plantarum and Bifidobacterium longum subspecies infantis in Papua New Guinean Infants: Protocol for a Randomized Controlled Trial.

Background: Childhood mortality in low- or middle-income countries (LMICs) remains a major public health concern, with infections being a leading cause of infant death. Probiotics have shown promise in reducing infection-related morbidity and mortality in preterm infants, but their use in newborns born at or near term in LMICs requires further investigation.

Objective: This study aims to assess the feasibility, safety, and initial outcomes of administering 1 of 2 synbiotic formulations or a placebo to newborns in the Eastern Highlands Province of Papua New Guinea.

Methods: Following ethics approvals in 2018 and 2019, and receipt of the synbiotic preparations in September 2020, healthy neonates (<72 h old; n=244) were recruited between October 2020 and June 2023 and randomly assigned in a double-blind manner (1:1:1) to receive an oral preparation containing Lactiplantibacillus plantarum, Bifidobacterium longum subspecies infantis, or placebo for 7 consecutive days. Follow-up continued for 6 months, with rectal swabs, stool, blood, saliva, and nasopharyngeal swabs collected before the intervention; on day 7; at age 2 weeks; and at ages 1, 3, 4, and 6 months. Ongoing analyses will assess probiotic gut colonization, bacterial nasopharyngeal carriage, and antibody responses to routine childhood vaccines (Hemophilus influenzae type b; hepatitis B; 13-valent pneumococcal conjugate vaccine; and diphtheria, tetanus, and whole-cell pertussis) as well as hospitalization and infection rates among the intervention groups compared to the placebo group.

Results: Recruitment began in October 2020, with the target sample size expanded from 195 to 240 in March 2023 owing to higher-than-anticipated loss to follow-up during the COVID-19 pandemic. Of the 244 enrolled infants, 218 (89.3%) completed the full 7-day synbiotic or placebo course, and 169 (69.3%) completed the study. All follow-up visits concluded in December 2023. Disruptions due to the COVID-19 pandemic led to family relocations outside the study area, preventing some infants (75/244, 30.7%) from completing the study. High rates of sample collection were achieved, with rectal swabs (1452/1474, 98.1%), nasopharyngeal swabs (1255/1262, 99.44%), saliva samples (881/882, 99.9%), and blood samples (876/882, 99.3%) successfully obtained at multiple time points. Data analysis is ongoing and expected to be completed by the end of 2025.

Conclusions: This study demonstrates that probiotic supplementation is feasible and safe in healthy infants in an LMIC such as Papua New Guinea. The findings from this study will inform the design of larger trials of probiotics and synbiotics to complement existing efforts to reduce infection-related infant mortality in LMICs, while also providing insights into their clinical, immunological, and microbiological impacts in infants.

Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620001369910; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620001369910.

International registered report identifier (irrid): DERR1-10.2196/73926.