NCT02249598.

Neisseria lactamica is a harmless coloniser of the infant respiratory tract, and has a mutually-excluding relationship with the pathogen Neisseria meningitidis. Here we report controlled human infection with genomically-defined N. lactamica and subsequent bacterial microevolution during 26 weeks of colonisation. We find that most mutations that occur during nasopharyngeal carriage are transient indels within repetitive tracts of putative phase-variable loci associated with host-microbe interactions (pgl and lgt) and iron acquisition (fetA promotor and hpuA). Recurrent polymorphisms occurred in genes associated with energy metabolism (nuoN, rssA) and the CRISPR-associated cas1. A gene encoding a large hypothetical protein was often mutated in 27% of the subjects. In volunteers who were naturally co-colonised with meningococci, recombination altered allelic identity in N. lactamica to resemble meningococcal alleles, including loci associated with metabolism, outer membrane proteins and immune response activators. Our results suggest that phase variable genes are often mutated during carriage-associated microevolution.

Recent work is adding to the growing evidence that genetic variation in pro-inflammatory cytokines has a role in susceptibility and survival in meningococcal disease. However, data need to be interpreted with caution as there are many confounding factors, sample sizes are often small and there are challenges in identifying suitable control groups.

Neisseria meningitidis causes significant disease in the form of severe sepsis syndrome or meningococcal meningitis. Owing to the susceptibility of the immune system in early life, the risk of disease after infection is significantly higher in infants. Thus far, vaccines targeted against meningococcal serogroups have struggled to provide lasting protection in young children. Even conjugate vaccines that are now routinely used in the immunization of infants require multiple dosing and the duration of protection has been shown to wane over time and require repeated booster doses. After briefly summarizing the current epidemiology according to age and serogroup, this article will consider the reasons for poor immunogenicity of vaccines in infants and will discuss the relative efficacy of the different vaccine types in this age group. It will then go on to consider strategies for optimizing the protection of infants against meningococcal disease.