Oral Presentation 25th International Pathogenic Neisseria Conference 2026

A Recombinant Neisseria lactamica Controlled Human Infection Model to Investigate Mucosal Immunity against Meningococcal Carriage (140438)

Tyween J Coutinho 1 , Matthew W Wilson 1 , Lauren Allen 2 , Diane F Gbesemete 1 , Adam P Dale 1 , Jay Lucidarme 3 , Ray Borrow 3 , Robert C Read 1 , Andrew Gorringe 2 , Jay R Laver 1
  1. Controlled Human Infection Group, The University Of Southampton, Southampton, HAMPSHIRE, United Kingdom
  2. Pathogen Immunology Group, United Kingdom Health Security Agency, Porton Down, WILTSHIRE, United Kingdom
  3. Meningococcal Reference Unit, United Kingdom Health Security Agency, Manchester, United Kingdom

The 2026 MenB outbreak in the UK demonstrates that, despite the availability of effective prophylaxis, this rapidly progressive sepsis syndrome remains a significant public health threat [1,2]. This highlights the need to complement individual-level protection strategies with interventions that reduce the prevalence of Neisseria meningitidis (Nmen) colonisation, upon which sub-capsular, protein-based vaccines appear to have limited effect [3]. Although the established correlate of protection against invasive meningococcal disease (IMD) is a strain-specific serum bactericidal antibody (SBA) titre >1:4 (using human complement) [4], data from animal models and controlled human infection (CHI) studies suggest that protection against nasopharyngeal carriage is mediated by distinct immune mechanisms within the mucosal compartment [5,6].

To deconvolute these protective mechanisms in the context of Nmen carriage, we propose a challenge/rechallenge CHI model using a mixture of genetically modified strains of the acapsulate commensal Neisseria lactamica (Nlac). Should colonisation with genetically modified Nlac (GM-Nlac) protect against subsequent homologous rechallenge, correlates of protection against colonisation can be identified, potentially informing future anti-meningococcal vaccine design.

Here, we demonstrate the surface expression of the meningococcal vaccine antigens Neisseria Adhesin A (NadA) and Factor H-binding protein (FHbp) on four distinct GM-Nlac strains derived from Nlac Y92-1009. Each strain expresses a common NadA variant and one of four FHbp variants (1.4, 1.13, 2.19, 3.45), representing the predominant variants among circulating UK Nmen strains. Using two flow cytometry assays, we show that antigen expression is not significantly reduced by site-directed mutagenesis of FHbp variants, while these mutations attenuate binding to human complement Factor H [7-10]. All GM-Nlac strains remain acutely susceptible to killing by normal human plasma.

We further show that meningococcal antigen expression does not significantly alter the cell-binding phenotype of GM-Nlac relative to wild type, suggesting no change in in vivo localisation. Finally, GM-Nlac remains refractory to genetic change even under idealised transformation conditions, minimising the risk of acquiring capsule synthesis genes from co-carried Nmen.

These strains have been combined into a multi-strain CHI inoculum (4xrNlac), for which a pilot safety and colonisation study is now underway.

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