Lactamica 9: Neisseria Lactamica Inoculation in Late Pregnancy

Microbial Colonization Clinical Trial

Official title: Lactamica 9: Defining Upper Respiratory Colonisation and Microbiome Evolution in Mother-infant Pairs Following Neisseria Lactamica Inoculation in Late Pregnancy

Status Completed

Clinical Trial Summary

Bacteria living in the nose and throat are generally harmless, but in some circumstances cause infections of the lungs (pneumonia) and brain (meningitis), which are among the commonest causes of death worldwide in young children (especially newborns). Babies with certain 'good' bacteria in the nose and throat are less likely to have infections by such 'bad' bacteria. Scientists have tried giving probiotics ('good' bacteria swallowed or sprayed into the nose) to pregnant women, new mothers and babies. These studies show that many probiotics are safe, but the amount of bacteria given is often unknown, and it is unclear if they work. A more precise option is to use controlled inoculation, by inserting a specific amount of particular 'good' bacteria into the nose under carefully controlled conditions. Our team have previously shown that inoculation with Neisseria lactamica ('good' bacteria) safely and reliably decreases Neisseria meningitidis ('bad' bacteria) in healthy adults' noses. N. lactamica is a type of harmless bacteria found in over 40% of children aged 1-2 years, but is uncommon in newborns and adults. We plan to inoculate 20 healthy pregnant women with N. lactamica nose drops, to find out if it is transferred to their babies after birth. Newborns become rapidly covered (colonised) with bacteria from their mothers, other people, and the environment, so this method mimics a natural way that babies receive bacteria. We will take saliva and nose swabs one day, one week, one month and four months after birth, and will use microbiological and genetic methods to study how the bacteria changes in babies compared with their mothers.

Clinical Trial Description

We plan to perform nasal inoculation with N. lactamica (wild type strain Y92-1009) in healthy pregnant women, to establish whether horizontal N. lactamica transfer to their neonates occurs, and to characterise the impact on the developing neonatal upper respiratory tract (URT) microbiome. If successful, this study will provide a novel model for inducing and capturing a natural colonisation event in neonates. Unlike traditional controlled human infection models, which capture inoculation-induced colonisation, this first-in-man model would study person-to-person commensal transmission, allowing comparison of microbiome changes and adaptive commensal microevolution in mother-infant pairs. We have already conducted relevant Patient and Public Involvement research, in which all 12 pregnant women interviewed reported approval for this proposed study, and 11 expressed that they would have been interested in taking part in such a study. We will approach healthy pregnant women in their second and third trimesters of pregnancy. Eligibility screening and enrolment will take place at 34+0 to 36+6 weeks gestation, and 20 women (not already colonised with N. lactamica) will be inoculated nasally with 10^5 colony forming units N. lactamica Y92-1009 at 36+0 to 37+6 weeks gestation. Samples will be obtained from new mothers (nasopharyngeal, oropharyngeal and saliva) and their neonates (nasopharyngeal and saliva) at 1 day, 1 week, 1 month and 4 months post-partum. If possible, and with the volunteer's consent, we will collect an umbilical cord blood sample at delivery and an infant venous blood sample at 1 month and 4 months post-partum, for storage and use in future studies. We will also collect a maternal venous blood sample at 4 months post-partum, as well as a saliva swab from any household contacts aged under 5 years. Any natural N. lactamica carriers identified at screening will not be inoculated, but will be followed-up with their neonates for biological sampling. Pharyngeal and saliva swabs will be suspended in storage medium, aliquoted and stored at -80°C. N. lactamica colonisation will be confirmed using selective agar, Gram stain, microscopy, and analytical profile index testing (and matrix-assisted laser desorption/ionization time-of-flight for inconclusive results). N. lactamica colonisation density will be quantified, isolates will be stored at -80°C, and Y92-1009 strain identity will be confirmed using targeted polymerase chain reaction (PCR). Microbiome analysis will be performed on thawed aliquots of paired mother-neonate samples, by DNA extraction, 16S ribosomal ribonucleic acid (rRNA) gene PCR, and amplicon sequencing. Poor quality and chimeric sequence reads will be removed, and high quality reads will be trimmed, aligned and clustered for taxonomic classification and statistical analysis. Paired maternal and neonatal isolates confirmed as N. lactamica Y92-1009 will be sequenced, and resulting genomes will be mapped to a complete N. lactamica Y92-1009 closed reference genome, to assess for evidence of distinct microevolution. We will also compare paired microbiome profiles to identify candidate organisms that are present in mothers and their infants. Paired mother-neonate sample aliquots will be thawed and plated onto selective media, and isolates of candidate species will be identified using Gram stain, microscopy, and other relevant microbiological tests. Resulting isolates will be sequenced and analysed for evidence of strain sharing between mothers and their neonates, suggesting horizontal transfer. ;

Related Conditions & MeSH terms

• Communicable Diseases
• Infections
• Microbial Colonization

• NCT number: NCT04784845
• Study type: Interventional
• Source: University of Southampton
• Status: Completed
• Phase: N/A
• Start date: October 1, 2021
• Completion date: July 12, 2022