The IMPROVE trial: IMpact of PRObiotic interVEntion in Papua New Guinean newborns.

INTERVENTION: Synbiotic 1, daily dose for 7 days (starting < 72 hours after birth): Lactobacillus plantarum ATCC 202195 (1 billion CFU) combined with 150 mg fructo‐oligosaccharide (FOS) with maltodextrin as excipient. Synbiotic 2, daily dose for 7 days (starting < 72 hours after birth): Bifidobacterium longum subspecies infantis (Bi‐26) (4.2 billion CFU) combined with human oligosaccharide (HMO) (1.2 g) with maltodextrin as excipient. Both supplements (investigational products) are supplied as lyophilized products in glass vials (one vial contains a single daily dose), and are reconstituted in 3 mL of breast milk expressed by the mother shortly before administration, or in 3 mL of sterile water if the mother cannot express. The full dose (3 mL suspension) is administered orally in droplets (like the oral polio vaccine) using a sterile pipette by a research nurse. The volume administered (full dose, or volume if less than 3 mL) will be recorded. Infants will be monitored for 30 min and a repeat dose will be administered if an infant vomits within this observation period. CONDITION: Clinical severe infection;pneumococcal infection; ; Clinical severe infection ; pneumococcal infection Infection ‐ Studies of infection and infectious agents PRIMARY OUTCOME: Feasibility of daily probiotic administration as measured by the proportion of children who successfully completed 7 days of the full daily supplementation (7 out of 7).; ; Research staff will administer the daily dose, record the volume administered (full 3 mL dose, or less), and monitor the infant for 30 min for vomiting. [Last day (day 7) of 7‐day schedule of once‐daily supplementation] Safety in terms of intolerance (diarrhoea, vomiting, abdominal distension, and weight gain) or probiotic sepsis during the supplementation period, leading to cessation of the study medication; ; ; Children will be checked daily for:; ‐ Vital signs including body temperature, pulse and respiratory rate; ‐ Presence of of signs/symptoms of severe infection (incl. poor feeding; lethargy; fever; hypothermia; convulsions; severe chest wall in‐drawing); ‐ Other clinical signs and symptoms of illness (incl. diarrhoea; vomiting; respiratory distress; infected umbilicus; jaundice; skin rashes/pustules; apnoea); ‐ Seeking medical attention (hospitalization; seeing a doctor) ; ; ; ; [24 hours after last day (day 7) of 7‐day schedule of once‐daily supplementation] SECONDARY OUTCOME: Gut colonisation by probiotic species & strains as measured and quantified by rt‐PCR in rectal swabs [Rectal swabs will be collected on the day of the 1st dosing (< 72 hours old) just before administration, on the day of the last dose (8‐10 days old), and when the child is 2 weeks old. ] Hospitalization rates ; ; Study children admitted to Goroka Hospital Pediatric Ward (the only tertiary facility in the Province) will undergo clinical assessment and examination by the admitting pediatric team. Study staff will check the ward for study children at least once daily. Detailed study morbidity forms will be completed to record symptoms, diagnosis and treatments, ; ; ; ] Mucosal IgA and IgG antibody responses induced by pneumococcal conjugate vaccine (PCV) measured in saliva 1 month after the 3rd dose[Saliva samples will be collected when children are 1 month old (before PCV vaccination) and 4 months old (1 month after completion of 3 doses of PCV). ] Nasopharyngeal carriage of S. pneumoniae and other respiratory bacteria, as assessed by routine bacterial culture and rt‐PCR of isolates obtained from routinely collected nasopharyngeal swabs [Nasopharyngeal swabs will be collected when children are 2 weeks and 1 month old (after completion of the intervention but before pneumococcal vaccination), and 4 months old (1 month after completion of 3 doses of pneumococcal conjugate vaccines). ] Rate of clinical severe infections ; [Children will be followed for the duration of the study until they are 6 months of age] Immunogenicity of childhood vaccines, including pneumococcal conjugate vaccine (PCV), Diphtheria, Tetanus and Pertussis (DTwP) vaccines, as assessed by IgG antibody concentrations against vaccine antigens measured by immuno‐assays in serum samples. [Serum samples will be collected when children are 1 month old (before DTwP and PCV vaccination) and 4 months old (1 month after completion of 3 doses of DTwP and PCV). ] Kinetics of colonization with probiotics species & strains as measured and quantified by rt‐PCR in rectal swabs for the duration of the study up to 6 months of age[In addition to rectal swabs collected for Secondary Outcome #1 to show gut colonization, additional samples will be collected when children are 1 month, 3 months, 4 months, and 6 months old to study kinetics of colonization ; ; Children presenting sick to the study clinic or hospital will checked for signs/symptoms of clinical severe infection, including: poor feeding; lethargy; convulsions; severe chest in‐drawing; fever; and/or hypothermia. ; When having any of the signs/symptoms, samples for septic work‐up will be collected and processed for clinical microbiology, including blood for culture; urine; nasopharyngeal swab; rectal swab; and based on clinical indication optionally CSF; umbilical swab; skin swab; ear discharge; and/or eye swab. ; ; Severe clinical infection is defined by having at least one of the listed symptoms/signs, and a positive sterile site culture or hospitalization with the intention to treat with parental antibiotics for at least 5 days.[Children will be followed for the duration of the study until they are 6 months of age] INCLUSION CRITERIA: ‐ Birth weight of at least 1.5 kg ‐ Postnatal age of less than 72 hours ‐ Feeding orally ‐ Resident within 60‐minute driving distance from Institute of Medical Research, Goroka ‐ Intention to stay in the study area for at least 6 months ‐ Parental written informed consent