Professor David Jackson
The research interests of the laboratory centre around the discovery and development of novel and innovative vaccine candidates. Using the techniques of chemical synthesis and molecular biology and/or a combination of both, we have developed vaccines for a variety of disease indications from infectious diseases to hormone blockade and substances of abuse including cocaine and methamphetamine.
A dominant strategy of these research efforts is to design the vaccine rationally; in other words to only include those components that are necessary for the desired and appropriate immune outcome. This means that we can remove unnecessary and sometimes dangerous components to provide safer vaccines that elicit antibody and/or cell-mediated immune responses. We also build into our vaccines an ability to be highly immunogenic, a feature that obviates the addition of extraneous adjuvants.
The laboratory has approximately ten members consisting of post doctoral fellows, research assistants and PhD students with undergraduate students providing a continuous flow of new talent each year. The laboratory operates through individual research efforts and through partnerships that are formed between one or more laboratory members and which are driven by unmet medical needs and the skills that are possessed by the various team members. Some of the projects and programs currently running in our laboratory are described below. Opportunities exist for motivated, intelligent and committed scientists to join the laboratory.
Innovative approaches to prepare synthetic, partially synthetic and natural product-based vaccines
Dr Weiguang Zeng, Ms Chinn Yi Wong and Ms Kylie
We have developed a modular approach to vaccine manufacture that involves the selective chemical ligation of individually assembled segments of a vaccine candidate. This modular approach offers a “plug and play” approach to vaccine development hastening the speed of new vaccine development and production. The major advantage of utilising this technology is that it provides the ability to incorporate conformational determinants such as those required for generation of effective antibody responses. This approach has the potential to make use of new chemistries and lends itself to the development of totally synthetic and partially synthetic vaccines as well as vaccines that are based on completely natural products.
Personnel: Dr Weiguang Zeng, Ms Kylie Horrocks, Ms Chinn Yi Wong
Lipopeptide-based adjuvanting systems
The low immunogenicity exhibited by most soluble protein antigens is in general due to the absence of any molecular signatures that are recognised by the immune system as being dangerous. We have developed a method that makes proteins highly immunogenic by using lipopeptides which target the TLR-2 receptor on dendritic cells. These lipopeptides are engineered to associate with native protein antigens which are then capable of inducing robust antibody and CD8+ T cell responses. The nature of the association between protein and lipopeptide provides a manufacturing advantage by reducing the need for more complex chemical interventions or modifications.
Personnel: Dr Brendon Chua, Mr Toshiki Sekiya
|Figure 1: Dendritic cells with internalised protein antigen (green) transported into the cell as a result of its association with lipopeptide. Cells were also stained for MHC Class II (Red) and a stain (blue) specific for the cell nucleus.|
Biolpolymer-based vaccine delivery systems
Polymer-based systems as vaccine delivery vehicles represent an emerging field of interest in vaccinology and include the advantages of biocompatibility and an ability to modify physical and chemical properties of polymers to obtain features appropriate to a particular vaccine. In collaboration with Professor David Mainwaring’s group at the Royal Melbourne Institute of Technology (RMIT) we are developing vaccine delivery systems using polymers. Features of the polymers that we are developing could enable controlled release of a vaccine over time eliminating the need for multiple vaccine doses.
Personnel: Dr Brendon Chua, Dr Weiguang Zeng
|Figure 2: Scanning Electron Micrograph of particles containing protein antigen.|
The innate immune system in the respiratory tract
Dr Amabel Tan and Ms Edin Mifsud
Introduction of infectious disease agents such as influenza A virus into the respiratory tract and pulmonary system results in the enlistment of immune cells, including neutrophils and macrophages, resulting in elevation of inflammatory and Th1 cytokines including IFN-γ and TNF-α. This immune activity is associated with broad spectrum, and antigen-independent, protection against subsequent challenge with mild and virulent influenza viruses. We are currently determining the mechanisms that underlie this phenomenon with a view to finding methods of reducing transmission of influenza at a population level.
Personnel: Dr Amabel Tan, Ms Edin Mifsud
A universal vaccine against influenza A
Dr Brendon Chua and Mr Toshiki Sekiya
A long standing interest of this laboratory is in developing vaccines which induce CD8+ T cell responses against the conserved regions of influenza in anticipation that we can develop a universal vaccine against the virus. We are investigating the ways in which HLA-diversity can be addressed using multi-epitope or protein-based vaccines in order to generate a CD8+ T cell-based vaccine which is effective in the population at large. We are also determining the features of CD8+ T cell function, location and magnitude that are associated with long-term protection against influenza A infection.
Personnel: Dr Amabel Tan, Ms Edin Mifsud, Dr Brendon Chua, Mr Toshiki Sekiya
Development of a Self-Adjuvanting Vaccine for Enterotoxigenic Escherichia coli (ETEC).
Infectious diarrhoea caused by ETEC is a major health problem worldwide. ETEC are the most common bacterial enteropathogens that are isolated from children less than 5 years of age in developing countries and account for several millions of cases of diarrhoea and several tens of thousands of deaths each year. ETEC are also the most common cause of traveller’s diarrhoea affecting travellers from industrialised countries to developing regions of the world. Colonisation factor antigen, heat-labile enterotoxin (LT) and heat-stable enterotoxin (ST) are main targets for development of an effective vaccine against ETEC. We have chemically synthesised an ST toxin that mimics the native toxin with full activity and now, in collaboration with Professor Roy Robins-Browne laboratory, we have developed totally synthetic lipopeptide-based vaccine constructs incorporating ST. The results of our study demonstrate that these vaccine candidates induce strong anti-ST antibody responses and that the antisera neutralise the toxicity of ST.
Personnel: Dr Weiguang Zeng, Ms Chinn Yi Wong
|Figure 3: Synthesis protocol for the assembly of correctly folded ST.|
Professor David C. Jackson
Dr Weiguang Zeng (Senior Research Officer)
Dr Brendon Chua (Research Officer)
Dr Amabel Tan (Research Officer)
Ms Chinn Yi Wong (Senior Research Assistant)
Ms Kylie Horrocks (PhD Student)
Ms Edin Mifsud (PhD Student)
Mr Toshiki Sekiya (PhD Student)
Mr Acep Riza Wijayadikusumah (Masters Student)
Professor Roy Robins-Browne, Department of Microbiology & Immunology, The University of Melbourne
Associate Professor Damian Purcell, Department of Microbiology & Immunology, The University of Melbourne
Associate Professor Joseph Torresi, The Department of Medicine, Austin Health, The University of Melbourne
Professor David Mainwaring, Royal Melbourne Institute of Technology
Dr Javed Agrewala, Institute of Microbial Technology, Chandigarh, India
Professor Stephen Turner, Department of Microbiology & Immunology, The University of Melbourne
Associate Professor Tim Stinear, Department of Microbiology & Immunology, The University of Melbourne
- Zeng W, Horrocks KJ, Robevska G, Wong CY, Azzopardi K, Tauschek M, Robins-Browne RM, Jackson DC. A Modular Approach to Assembly of Totally Synthetic Self-adjuvanting Lipopeptide-based Vaccines Allows Conformational Epitope Binding. The Journal of Biological Chemistry 2011; 286: 12944-51.
- Zeng W, Eriksson EM, Lew A, Jackson DC. Lipidation of intact proteins produces highly immunogenic vaccine candidates. Mol Immunol 2011; 48: 490-6.
- Miles JJ, Thammanichanond D, Moneer S, Nivarth UK, Kjer-Nielsen L, Tracy SL, Aitken CK, Brennan RM, Zeng W, Marquart L, Jackson D, Burrows SR, Bowden DS, Torresi J, Hellard M, Rossjohn J, McCluskey J, Bharadwaj M. Antigen-driven patterns of TCR bias are shared across diverse outcomes of human hepatitis C virus infection. The Journal of Immunology 2011;186: 901-12.
- Zeng W, Eriksson E, Chua B, Grollo L, Jackson DC. Structural requirement for the agonist activity of the TLR2 ligand Pam2Cys. Amino Acids 2010; 39: 471-80.
- Yang X, Adda CG, MacRaild CA, Low A, Zhang X, Zeng W, Jackson DC, Anders RF, Norton RS. Identification of key residues involved in fibril formation by the conserved N-terminal region of Plasmodium falciparum merozoite surface protein 2 (MSP2). Biochimie 2010; 92: 1287-95.
- Pejoski D, Zeng W, Rockman S, Brown LE, Jackson DC. A lipopeptide based on the M2 and HA proteins of influenza A viruses induces protective antibody. Immunol Cell Biol 2010; 88: 605-11.
- Gowans EJ, Roberts S, Jones K, Dinatale I, Latour PA, Chua B, Eriksson EM, Chin R, Li S, Wall DM, Sparrow RL, Moloney J, Loudovaris M, Ffrench R, Prince HM, Hart D, Zeng W, Torresi J, Brown LE, Jackson DC. A phase I clinical trial of dendritic cell immunotherapy in HCV-infected individuals. J Hepatol 2010; 53: 599-607.
- Fosang AJ, Last K, Stanton H, Golub SB, Little CB, Brown L, Jackson DC. Neoepitope antibodies against MMP-cleaved and aggrecanase-cleaved aggrecan. Methods Mol Biol 2010; 622: 312-47.
- Zeng W, Eriksson E, Chua BY, Grollo L, Jackson DC. Structure-activity relationships of the TLR2 ligand Pam2Cys. European Journal of Immunology supplement 2009; 1/09 39: S1.S60
- Read AJ, Casey JL, Coley AM, Foley M, Gauci CG, Jackson DC, Lightowlers MW. Isolation of antibodies specific to a single conformation-dependant antigenic determinant on the EG95 hydatid vaccine. Vaccine 2009; 27: 1024-31.
- Ng WC, Gilbertson B, Lim B, Zeng W, Jackson DC, Brown LE. Lipopeptide vaccines illustrate the potential role of subtype-crossreactive T cells in the control of highly virulent influenza. Influenza Other Respi Viruses 2009; 3: 177-82.
- Macdonald WA, Chen Z, Gras S, Archbold JK, Tynan FE, Clements CS, Bharadwaj M, Kjer-Nielsen L, Saunders PM, Wilce MCJ, Crawford F, Stadinsky B, Jackson D, Brooks AG, Purcell AW, Kappler JW, Burrows SR, Rossjohn J, McCluskey J. T cell allorecognition via molecular mimicry. Immunity 2009; 31: 849-51.
- La Gruta N, Kelso A, Brown LE, Chen W, Jackson DC, Turner SJ. Role of CD8(+) T-cell immunity in influenza infection: potential use in future vaccine development. Expert Rev Respir Med 2009; 3: 523-37.
- Kinsey BM, Jackson DC, Orson FM. Anti-drug vaccines to treat substance abuse. Immunology and Cell Biology 2009; 87: 309-14.
- de Kauwe AL, Chen Z, Anderson RP, Keech CL, Price JD, Wijburg O, Jackson DC, Ladhams J, Allison J, McCluskey J. Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells. The Journal of Immunology 2009; 182: 7440-50.
- Bharadwaj M, Thammanichanond D, Aitken CK, Moneer S, Drummer HE, Tracy S, Holdsworth R, Bowden S, Jackson D, Hellard M, Toressi J, McCluskey J. TCD8 response in diverse outcomes of recurrent exposure to hepatitis C virus. Immunology and Cell Biology 2009; 87: 464-72.