Title: Characterising human CD4+ effector T cell responses following experimentally-induced colonisation with genetically-modified Neisseria lactamica expressing the meningococcal vaccine antigen, Neisseria adhesin A.
Funder: The Academy of Medical Sciences

Abstract: Future vaccines against disease caused by Neisseria meningitis (Nmen), Streptococcus pneumoniae and Haemophilus influenzae should be low-cost strategies which induce herd protection against upper respiratory tract (URT) pathogen acquisition. One strategy could be to exploit naturally-occurring protective relationships between pathogenic and commensal organisms. Experimental colonisation of humans with N. lactamica (Nlac) protects against Nmen colonisation and results in generation of anti-Nmen humoral and memory B cell responses, suggesting that protection against Nmen colonisation may be due to formation of cross-reactive adaptive immunity. Furthermore, Nmen-specific adaptive immune responses generated by Nlac colonisation were enhanced by genetically-modified Nlac (GM-Nlac) engineered to express the meningococcal vaccine antigen, Neisseria adhesin A (NadA). Anti-Nmen protein vaccine bactericidal antibodies do not protect against Nmen colonisation but antigen-specific Th17-polarised CD4+ effector T cell (Teff) responses have been shown to protect against URT pathobiont colonisation. If induction of Nmen-cross-reactive CD4+ Teff responses is the mechanism by which Nlac colonisation prevents Nmen colonisation, we would hypothesise that NadA-specific CD4+ Teff responses generated following colonisation with NadA-expressing Nlac would be of Th17 effector phenotype. Addressing the outlined hypothesis, my aim is to enumerate and characterise the effector phenotype of NadA-specific CD4+ Teff generated following colonisation with NadA-expressing Nlac. To meet this aim, for the first objective I will optimise a flow cytometry-based assay to characterise NadA-specific CD4+ Teff using CD154 magnetic-enrichment. For my second objective, I will assess the frequency and effector phenotype of NadA-specific CD4+ Teff in PBMC of participants inoculated and colonised with NadA-expressing Nlac or isogenic control.

Lay abstract: Neisseria lactamica is a ‘good bacteria’ that lives in the nose and throat of young children. Its presence is associated with lower rates of disease caused by Neisseria meningitidis, a ‘bad bacteria’ that causes severe meningitidis and blood stream infections. In previous work, we showed that we could reduce the number of people carrying the bad bacteria by introducing the good bacteria harmlessly into their noses. Although we do not yet understand the reason this phenomenon occurs, it is possible that immune responses mounted against the good bacteria interact with the bad bacteria and result in their eradication. Indeed, we recently demonstrated that introduction of the good bacteria into the noses of healthy adults resulted in the formation of immune responses that reacted with the bad bacteria. In addition, we found that the potency of these responses was enhanced by harmlessly genetically modifying the good bacteria so that it included a single element of the bad bacteria on its surface. Having established that colonisation with the good bacteria generates immune responses to the bad bacteria, we would now like to characterise these responses in more detail. Specifically, we want to assess a type of immune response called the ‘T cell’ response, which has been found to protect against colonisation with other bad bacteria. This work will provide insights into the immune mechanisms that protect against colonisation with bad bacteria and will lay the necessary foundations to develop and test future vaccines designed to specifically prevent colonisation with bad bacteria.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION