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Development of new biological adjuvants and vaccines for prevention of bacterial infections


Project Description

Research interests/description of main research theme:

The main research theme is developing new approaches to vaccinate against infectious diseases.

Immunization is a major way to prevent infectious diseases in man and other animals. In order to generate protective immunity it is important to generate the appropriate type of immunity (e.g. antibody vs cellular immunity). The structural features of microbial antigens play a fundamental role the way immune system responds. In this project bacterial protein toxins will be developed as adjuvants to develop appropriate immune responses in vaccines for protection against infectious diseases in man and animals. Preliminary data demonstrates that bacterial pore-forming toxins such as pneumolysin (from S.pneumoniae), suilysin (from S.suis) and others act as potent activators of the immune system. We have eliminated the toxicity of these proteins by deletion of key amino acids from the proteins that are crucial to the pore formation process (1). There are also natural non-toxic variants of pneumolysin in some pneumococcal strains and these will be cloned and expressed to allow evaluation of biological activity (2). We have shown that these engineered or natural toxoids stimulate cell signalling events that generate antibody and T-cell responses. We have also shown that the membrane-binding domain of the toxin (C-terminal domain) can be expressed separately and also acts as an adjuvant for proteins that are linked to it (3). Furthermore, we have identified several naturally occurring polymorphisms affecting the haemolytic activity of these pore forming toxins (2). An advantage of use of these genetically engineered and naturally occurring toxoids to modulate immune response is that they can be coupled with other proteins, which then provides impressive immune responses to the carried protein. Vaccines generated using this technology will then be used to assess protective efficacy against infectious challenges with multiple serotypes of the pneumococcus in animal models of infection.

Person Specification
Applicants should have a strong background in biological/medical science, and ideally a background in immunology. They should have a commitment to research in infectious disease and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply
Informal enquiries should be directed to Professor Tim Mitchell ()

Applications should be directed to https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx

To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

Funding Notes

Funded through MIBTP
You can apply for a 4 year BBSRC-funded doctoral fellowship (MIBTP): View Website
Eligibility: UK/EU nationals, residence in the UK is NOT a pre-requisite.

References

References
1. Kirkham L-AS, Kerr AR, Douce GR, Paterson GK, Dilts DA, Liu D-F, et al. Construction and Immunological Characterization of a Novel Nontoxic Protective Pneumolysin Mutant for Use in Future Pneumococcal Vaccines. Infect Immun. 2006;74(1):586-93.
2. Kirkham L-AS, Jefferies JMC, Kerr AR, Jing Y, Clarke SC, Smith A, et al. Identification of Invasive Serotype 1 Pneumococcal Isolates That Express Nonhemolytic Pneumolysin. J Clin Microbiol. 2006;44(1):151-9.
3. Pope C, Oliver EH, Ma J, Langton Hewer C, Mitchell TJ, Finn A. Genetic conjugation of components in two pneumococcal fusion protein vaccines enhances paediatric mucosal immune responses. Vaccine. 2015;33(14):1711-8.

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