Colonisation dynamics of Bordetella pertussis and Neisseria lactamica in the nasopharynx during experimental asymptomatic infection in humans

Abstract

The establishment of colonisation in the nasopharynx is a prerequisite stage preceding infections due to nasopharyngeal bacteria. The resurgence in the reported cases of pertussis, a highly infectious respiratory disease caused by Bordetella pertussis (Bp), has been partly attributed to a failure of the current acellular pertussis vaccines to protect against asymptomatic infection. Following the introduction of the 4-component Meningococcal B vaccine (4CMenB), studies have shown a limited impact on serogroup B Neisseria meningitidis carriage. However, carriage of the commensal bacteria Neisseria lactamica (Nlac) has been shown to protect against the carriage of N. meningitidis. Failure of vaccines to prevent asymptomatic carriage could mean that these bacteria will continue to circulate in the population causing disease, and thus continue to pose a public health challenge. In recent years it has become recognised that assessing protection against asymptomatic infection (i.e. by measuring colonisation density) should be included as an endpoint in future vaccine trials, and controlled human infection studies could support this. The aim of this work was to study the asymptomatic colonisation dynamics of Bp and genetically modified (GM) Nlac (expressing NadA from serogroup B N. meningitidis) in healthy adults using controlled human infection models (CHIM).
The aims of the pertussis CHIM were firstly to determine whether asymptomatic carriage could be induced in healthy adults and secondly, to explore the relationship between baseline immunity and Bp carriage. The results from phase A of the study, the first CHIM using wild-type Bp, demonstrated that asymptomatic infection could be induced in healthy adults. A dose of 105 colony-forming units/mL of Bp induced nasopharyngeal colonisation in 80% of volunteers. In Phase B, only 37% of volunteers became colonised, and serology showed a significant inverse correlation between baseline serum anti-PT IgG and the quantity of Bp detected on day 14. Results also showed that prior intra-nasal challenge with Bp significantly reduced the quantity of Bp detected in nasopharyngeal samples after re-challenge with the same strain.
The aim of GM-Nlac CHIM was to examine if the anti-meningococcal effect of Nlac could be enhanced using a GM strain expressing the meningococcal protein Neisseria adhesin A (NadA), which is also an immunogenic component of 4CMenB vaccine antigen. The results from qPCR of throat swabs showed that the quantity of GM-Nlac detected in throat swabs was higher in throat swabs collected from volunteers who received the NadA expressing strain compared to the control group who received a wild-type equivalent strain. However, these differences were not statistically significant. Immunological data generated from the study showed that carriage of GM-Nlac expressing NadA resulted in the generation of NadA-specific immune responses.
The controlled human infection studies described here have the potential to be used in future studies to support the development of new vaccines such as by; (i) assessing the impact of bacterial surface proteins on colonisation density and development of immunity, (ii) assessing the ability of vaccines candidates to protect against asymptomatic infection.

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Identifiers

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

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

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