Controlled human infection with Neisseria lactamica

Abstract

Meningococcal disease is a globally important cause of mortality and morbidity,
particularly in the meningitis belt of Sub-Saharan Africa. The causative agent, Neisseria
meningitidis, commonly colonises the human nasopharynx asymptomatically, but
occasionally becomes invasive, resulting in fulminant disease.

Neisseria lactamica is a closely related bacterium which colonises the same niche,
but is non-pathogenic. Colonisation with N. lactamica may provide protection from
colonisation with N. meningitidis, and from meningococcal disease. A controlled human
infection model has previously been developed, using nasal inoculation to induce
nasopharyngeal colonisation with N. lactamica, with a subsequent reduction in N.
meningitidis carriage demonstrated.

This thesis describes four controlled human infection studies designed to optimise
and further develop this model. In the first study, the impact of duration of colonisation on
immunogenicity was assessed by allowing participants to remain colonised for a short, or
longer period after inoculation. The use of an increased inoculum dose, antibiotic
clearance of colonisation, and the shedding of bacteria were also investigated.

The second study involved challenge with a genetically modified strain of N.
lactamica expressing the meningococcal antigen NadA. This study aimed to investigate
the immunological impact of the expression of a bespoke, heterologous antigen during
asymptomatic colonisation.

The final two studies investigated the use of a lyophilised preparation of N.
lactamica, aiming to make the model feasible for use in a lower resourced setting, beyond
a reliable cold-chain. Dose-ranging studies were conducted in the UK, and subsequently
in Mali, within the meningitis belt. The impact of lyophilisation on the ability of N. lactamica
to colonise the nasopharynx, and to induce an immune response, was investigated.

These studies have confirmed that intranasal inoculation with both wild-type and
genetically modified strains of N. lactamica safely induces long-standing nasopharyngeal
colonisation in a high proportion of individuals. This colonisation induces N. lactamica
specific and cross-reactive N. meningitidis specific immune responses. An immune
response specific to a heterologous antigen can be induced by expression of that antigen
by recombinant N. lactamica. Lyophilisation of N. lactamica is safe, feasible, and does not
reduce colonisation potential or immunogenicity. Use of the model within the meningitis
belt is feasible, safe and induces a similar pattern of colonisation and immunogenicity.

Future studies will investigate the impact of N. lactamica colonisation on
meningococcal carriage and disease in the meningitis belt, and the use of further genetic
manipulation to improve cross-reactive immunity to N. meningitidis, with the overall aim of
developing improved strategies for protection from meningococcal disease.

More information

Identifiers

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

ORCID for Saul Faust: orcid.org/0000-0003-3410-7642

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