STUDIES OF VARIABLE OR CONSERVED SURFACE PROTEIN SITES OF NEISSERIA MENINGITIDIS AS EPITOPES FOR STRAIN-SPECIFIC VACCINES OR BROAD-STRAIN (UNIVERSAL) VACCINES

Summary

The gram-negative Neisseria Meningititis (NM) remains a significant microbial problem and particularly lethal for the very young. Serogroup B strains are particularly troublesome and B vaccines are not fully protective. Especially worrisome is that NMs close relative Neisseria Gonococcus (NG) has joined the list of dirty dozen top microbes globally, having developed multi-drug resistance (MDR) and is spreading. Whether NG could share this resistance with NM is of obvious concern. Our studies are holistically addressing both strain specific targeting and more universal broad-strain targeting approaches and perhaps for which the latter may also be for valuable for defense against MDR-NG.

Supervisor(s)

Dr Garry Lynch

Research Location

Camperdown - Central Clinical School

Program Type

Masters/PHD

Synopsis

Background: Infection by Neisseria Meningititis (NM) remains a major cause of meningitis disease and death. While vaccinations have been developed and effective for many strains of NM, exposure to prominent strains such as strain B and newly evolved NM strains remain as a significant health risks. This highlights a need for new and more universally protective vaccines than are currently available. NM is also a close relative of NeisseriaGonococcus, which has developed multi-drug resistance. Our studies are directed at understanding and defining both strain-specific and broad-strain immune targets for adaptive antibody immunity. From which we are applying a protein structure-based approach for our vaccine design. Firstly, alternately highly-variable or highly conserved sites of the target surface protein of Neisseria Meningitidis (NM), are identified. Those sites are then profiled for IEDB immune potential, and mapped to reveal exposed likelihood for antibody targeting. Peptides and Protein constructs of the most promising sites are then made and tested in immunoassays for antibody targeting. This is followed by Bioassay to reveal functional protection. Panels of such validated sites thus enable the design of alternately strain-specific as well as broad-strain ‘universal' vaccines. The latter for potentially protection against all strains of NM, perhaps even strains yet to appear. In this study, which does not use live bacteria, the student will use bioinformatics, in silico (i.e., computer) molecular-modeling, recombinant and peptide technologies to identify and study alternately variable or conserved sites that can be targeted for strain-specific immune dominant attack, or more broadly by natural occurring human antibodies for broad-strain targeting. This is an exciting time for the project with already a number of promising protein sites already identified, and peptides in hand for immunoassay testing and proof of principle validation. This project involves study aspects from each part of our in-house biodesign pipeline, from initial mapping and structural analysis realization of candidate sites, through to immune-validation of already defined surface meningococcal epitopes, and edging closer to making the idea of universal vaccines a reality. In addition to the biological studies if the student is interested in applying digital or other art based mediums to visualize the proteins, cells and bacteria involved, there is scope within the study for a side BioVisualisation component to assist in development concepts, understanding and communication. Aims of this project include providing a platform for a study of distinction, and for the generation of solid data and findings worthy of publication.Approach:
Significance:
Collaborators: Professor Robert Booy (Medicine, Westmead Childrens Hospital, Head of Clinical Research, National Centre for Immunisation Research and Surveillance (NCIRS), Dr William Bret Church (Pharmacy), A/Prof John Sullivan (Medicine), Prof Hans Zoellner (Dentistry), A/Prof Peter Williamson (SOLES, Science).

Additional Information

Techniques can involve: Proteomics, cell and protein fractionation, electrophoresis, immunoblotting, immunoprecipitation, multiplex-analysis. bioinformatics, computational modelling, analysis and design of protein structures. Computational and wet laboratory studies of antibodies and antibody-binding, recombinant proteins, peptide studies and analyses; mass spectrometry, x-ray crystallisation, cryo-electron microscopy, surface Plasmon resonance.
Relevant References:
1. Lynch, G et al Seasoned adaptive antibody immunity for highly pathogenic pandemic influenza in humans. Immunol Cell Biol 90: 149-158. (2012).
2. Lynch, G.W., Selleck, P. & Sullivan, J.S. Acquired heterosubtypic antibodies in human
immunity for avian H5N1 influenza. J Mol Genet Med 3, 205-209 (2009).

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Keywords

bacteria, gram-negative, Neisseria, Meningitidis, Meningococcus, Gonococcus, MDR, antibody, Vaccine, protein, structure, Infectious Disease, Immunology.

Opportunity ID

The opportunity ID for this research opportunity is: 2591

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