Controlled human infection model of Neisseria lactamica in late pregnancy investigating mother-to-infant transmission in the UK: a single-arm pilot trial.

Abstract

BACKGROUND: The infant respiratory microbiome is derived largely from the mother and is associated with downstream health and disease. Manipulating maternal respiratory flora peripartum to influence the infant microbiome has not previously been investigated. Neisseria lactamica is a harmless pharyngeal commensal that correlates inversely with Neisseria meningitidis carriage and disease. Intranasal N lactamica inoculation is a safe and well characterised controlled human infection model (CHIM) in non-pregnant healthy adults. We hypothesised that N lactamica inoculation in pregnancy induces mother-to-infant N lactamica transmission postnatally. METHODS: In this single-arm trial, 21 healthy pregnant female participants aged 18 years or older were inoculated at 36-38 weeks' gestation with 105 colony-forming units of N lactamica Y92-1009 at University Hospital Southampton Clinical Research Facility, Southampton, UK. N lactamica selective culture, genome sequencing, and serological testing were performed on maternal and infant oral, nasopharyngeal, breastmilk, and serum samples over 15 weeks postpartum. Seven female participants naturally colonised with N lactamica at baseline were followed up, but not inoculated. Oral samples were obtained from 12 cohabiting siblings younger than 5 years. The primary endpoint was infant N lactamica colonisation. This study was registered with ClinicalTrials.gov, NCT04784845, and is now complete. FINDINGS: Between Oct 25, 2021, and March 7, 2022, 31 adult female participants (median age 33·5 years [range 23·1-39·9]; 26 [84%] were White, British) were screened and enrolled, of whom seven were already colonised with N lactamica. After exclusion of three participants, 21 participants were inoculated, of whom 15 (71%) became N lactamica-colonised, and no sustained N lactamica Y92-1009 transmission to their infants was observed. Conversely, non-Y92-1009 N lactamica strain sharing was observed in four (57%) of seven uninoculated mother-sibling pairs, and Moraxella catarrhalis strain sharing in nine (38%) of 24 mother-infant pairs completing the study. Anti-N lactamica serum IgG titres increased in seven (88%) of eight N lactamica Y92-1009-colonised female participants, but none of their infants (where paired sera were available). There were no serious adverse reactions to the inoculum. INTERPRETATION: As the world's first perinatal CHIM, this trial demonstrates that this model in pregnancy is feasible, and that N lactamica Y92-1009 can safely and efficiently colonise pregnant individuals. Lack of sustained mother-to-infant N lactamica transmission, despite evidence supporting mother-to-infant M catarrhalis and sibling-to-mother N lactamica transmission, challenges conventional perceptions of infants as passive recipients of maternal microbes, suggesting that respiratory commensal transmission is selective and microbe-specific. FUNDING: Medical Research Council and National Institute for Health Research Southampton Biomedical Research Centre.