Lactamica 9: defining upper respiratory colonisation and microbiome evolution in mother-infant pairs following Neisseria lactamica inoculation in late pregnancy

Abstract

This doctoral thesis presents the first ever perinatal controlled human infection (CHI) trial. A growing body of research has suggested a role for early life upper respiratory tract (URT) host-microbiome interactions in downstream respiratory health, although interventional human studies are lacking. To address this gap, a CHI in pregnancy was designed, aiming to provide a novel interventional model for investigating mother-to-infant commensal and broader microbiome transmission. The hypothesis was that nasal inoculation in late pregnancy with the harmless commensal Neisseria lactamica would result in maternal colonisation and mother-to-infant URT transmission. The study also explored the feasibility, acceptability and safety of perinatal CHI, as well as serological and microbiome effects of N. lactamica inoculation in mother-infant pairs and co-habiting young children. This pilot study suggests that nasal inoculation of pregnant women with N. lactamica is safe and acceptable. Although most inoculated women (75%, 15/20) became colonised with N. lactamica, with no reported serious adverse reactions, sustained mother-to-infant transmission was not observed. Conversely, mother-infant strain-sharing of other naturally-occurring commensals, such as Moraxella catarrhalis, was seen, along with broader microbiome sharing. Additionally, the study provides new evidence supporting transmission of N. lactamica from children aged 1 to 5 years to their mothers, but not vice versa. Taken together, these results challenge conventional perceptions of infants as passive recipients of maternal microbes, suggesting instead that commensal transmission is microbe-specific. Microbiome analyses via 16S rRNA gene sequencing indicated that maternal N. lactamica inoculation was associated with altered maternal and infant URT microbiome diversity, although the mechanisms underlying these changes remain unclear. The existing literature and novel findings presented in this thesis highlight the complexities underlying maternal-infant-microbial mucosal and systemic interactions. While important unanswered questions remain, this study is an important proof-of-concept that may inform future CHI trials in early life, with a view to improving understanding and ultimately unlocking microbiomebased interventions to improve infant health.

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Identifiers

ORCID for Anastasia Theodosiou: orcid.org/0000-0002-0096-4825

ORCID for Chrissie Jones: orcid.org/0000-0003-1523-2368

ORCID for Robert Read: orcid.org/0000-0002-4297-6728

ORCID for Jay Laver: orcid.org/0000-0003-3314-5989

ORCID for David Cleary: orcid.org/0000-0003-4533-0700

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