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

Background<br/>The infant respiratory microbiome is derived largely from its 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 (Nlac) is a harmless pharyngeal commensal that correlates inversely with N. meningitidis carriage and disease. Intranasal Nlac inoculation is a safe and well-characterised controlled human infection model (CHIM) in non-pregnant healthy adults. We hypothesised that Nlac inoculation in pregnancy induces mother-to-infant Nlac transmission postnatally.<br/>Methods<br/>Twenty-one healthy pregnant women were inoculated at 36-38 weeks’ gestation with colony-forming units Nlac Y92-1009 at University Hospital Southampton Clinical Research Facility, UK (NCT04784845, closed to participants). Nlac selective culture, genome sequencing and serology were performed on maternal and infant oral, nasopharyngeal, breastmilk and serum samples over 15 weeks postpartum. Seven women naturally-colonised with Nlac at baseline were followed-up, but not inoculated. Oral samples were obtained from 12 one- to five-year-old siblings. The primary endpoint was infant Nlac colonisation.<br/>Findings<br/>Although 15/21 (71%) inoculated women became Nlac-colonised, no sustained Nlac Y92-1009 transmission to their infants was observed. Conversely, non-Y92-1009 Nlac strain-sharing was observed in 4/7 (57%) uninoculated mother-sibling pairs, and M. catarrhalis (Mcat) strain sharing in 9/24 (38%) mother-infant pairs completing the study. Anti-Nlac serum IgG titres increased in 7/8 (88%) Nlac Y92-1009-colonised women, but none of their infants (where paired sera were available). There were no serious adverse reactions to the inoculum.<br/><br/>Interpretation<br/>This first-in-human trial demonstrates that CHIM in pregnancy is feasible, and that Nlac Y92-1009 can safely and efficiently colonise pregnant women. Lack of sustained mother-to-infant<br/>Nlac transmission, despite evidence supporting mother-to-infant Mcat and sibling-to-mother Nlac transmission, challenges conventional perceptions of infants as passive recipients of maternal microbes, suggesting that respiratory commensal transmission is selective and microbe-specific.<br/><br/>