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Vaccine and Infectious Diseases Laboratory

Laboratory Head

  • Professor Magdalena Plebanski

Staff

  • Dr Sue Xiang
  • Ms Jennifer Hanley
  • Ms Gabriela Minigo
  • Ms Ester Lopez 
     

Graduate students

  • Ms Karen Scalzo
  • Ms Cassandra David
  • Ms Anja Scholzen

Vaccines against infectious diseases and cancer

Parasitic diseases such as malaria kill one child every ten seconds in endemic areas. Cancer is the largest killer, both in the First and Third worlds, with one third of individuals affected in their lifetime. Viral and parasitic diseases as well as cancer remain largely difficult to eliminate with drug therapy. There are no vaccines for many of these diseases.

The Vaccine and Infectious Diseases Laboratory has continued to develop a two tier approach to generate effective vaccines: 1) Develop novel carrier adjuvants to target antigens to dendritic cells for the induction of effective immunity that protects against cancer and malaria and 2) Understand why other vaccines have not worked in individuals once they already have cancer or harbour the malaria parasite. We have discovered this is largely because these pathogens engage the mechanisms the body would normally use to regulate itself and decrease immune responses. We are now at a very exciting stage, having developed a new powerful platform vaccine approach able to protect against malaria, Respiratory Syncytial Virus and a range of experimental cancers, as well as uncovered a range of immune suppressor mechanisms, including a new suppressor T cells, and a specific dendritic cell subtype susceptible to parasite down-modulation. Together these two strands of research help us to design uniquely potent vaccines for therapy of human cancers and infectious diseases like malaria. We will continue to study why our dendritic cell carrier-adjuvant DCtag is so powerful, to uncover new principles of host regonistion of danger, and progress these powerful DCtag vaccines towards human trials.

Dendritic cells: vaccines and immune evasion

Dendritic cells (DC) are central to activating immune responses. This year we have continued to investigate how dendritic cells can induce protective immunity in malaria. We have discovered the malaria parasite can affect the function of dendritic cells in an attempt to prevent the induction of immune responses that can destroy it. However, we have also found ways to stimulate the immune responses via dendritic cells in vaccination protocols, so that protective immune responses can be induced, and the parasite is eliminated. Basic insights into this battle of wits between parasites and the host immune system are used directly to help optimise vaccine design.

Generally low T cell responses characterise individuals living in malaria endemic areas. Deficiencies in priming or re-stimulating memory T cells, as well as active suppression may contribute to maintain sub-optimal naturally induced immunity in these populations. Mature DCs are fully competent antigen presenting cells (APCs) and co-stimulatory cells and the ability of the parasite to interfere with their maturation would likely affect their ability to present antigen and activate both naïve and potentially memory T cells. A number of bacteria, viruses and parasites have been recently described to affect DC function and in turn compromise induction of antigen-specific T cell function. Previous studies in vitro using human DCs suggested interaction with parasitised red cells can arrest their maturation. This year it was shown that murine DCs are susceptible to a similar maturation arrest in vitro. The consequences of this interaction for the in vivo priming compared to maintenance of T cell immunity were explored using an immunisation model with Ovalbumin. In this same model, selected CD8 and CD4 T cell epitopes were further compared. The results of this study suggested that the blood-stage parasite selectively affects the ability of DC to prime CD8 T cells. These findings may explain the long standing observation of particularly low numbers of CD8 T cells to malaria antigens in malaria exposed donors, even in the face of high level exposure. It also suggested that whereas liver-stage malaria could benefit from this potential immune evasion mechanism, the fact that DCs ability to induce CD4 T cells was not affected by interaction with blood-stage parasites could suggest that DC would still be able to induce blood-stage protection.

The role of dendritic cells (DCs) in the induction of malaria immunity is unclear. This hypothesis was tested directly by pulsing DCs with intact Plasmodium yoelii parasitised red blood cells and immunising animals to test for induction of protection. Successful induction of protection was observed against lethal blood-stage malaria challenge. Protection was absent in IL-12 knockout animals, suggesting an important role for this cytokine. Immunisation was able to induce antigen specific interferon gamma (IFN gamma) and interleukin 4 (IL-4) T cell responses as well as significant anti-parasite antibody responses. Similar protection was observed 10, 30 and 120 days after a single immunisation. Cross-protection was achieved between two different malaria strains. Together these results suggested that DC may not only play a central role in immunity against blood-stage malaria, but may in fact induce a highly attractive pattern of protection after vaccination: single dose, cross-strain specific, and long-lasting.

On this basis a method was developed for the simple and practical targeting DC in vivo by injecting them with an inert carrier adjuvant (DCtag). By conjugating either malaria blood-stage lysates or a recombinant protein MSP4/5 (in collaboration with Prof. Coppel) to this simple solid inert carrier, we were able to reproduce this pattern of protection: long lasting protective immunity after a single administration.

An additional attractive feature of this carrier approach is that it can be used with any protein, or protein combination, without having to develop new vectors, providing thus a rapid test for the multiplicity of antigens proposed as components for a multi-protein malaria vaccine. Interestingly, and surprisingly for blood-stage malaria vaccines, protection was observed in the absence of a productive parasite stage – ie. whereas other vaccines protect against death after a period of high levels of parasites in the blood, the DC targeting carrier vaccine induces protection in the absence of detectable parasites. Current efforts include testing of combinations of antigens for malaria and other diseases and several collaborations are being explored. Collaborative studies with the Dr Scheerlinck at the Centre of Animal Biotechnology have shown the DCtag carrier is also an adjuvant in sheep, showing great promise as a vector for use in a variety of species.

Balance of protective immunity and regulation: malaria and cancer induce suppressor T cells

Malaria parasites not only affect DC but can directly turn off potentially protective cells induced previously by vaccines or natural exposure. Our work in malaria is further uncovering the mechanisms by which parasites, viruses and cancer cells can sabotage the immune response. 2001 saw the discovery in our laboratory of a new type of suppressor cell, which may be a critical regulator of immunity to a variety of pathogens such as the malaria parasite, HIV, tuberculosis and cancer, as well as potentially involved in the maintenance of self-tolerance (which prevents the onset of autoimmune disease, for example diabetes). We are continuing to characterise this (and other) suppressor cells and design ways to induce them, or turn them off, for human therapy and vaccination.

Victoria has many excellent internationally competitive cancer research groups developing vaccines. There are at least four different approaches: using cancer cells themselves; using stimulatory autologous DC fed with cancer derived immunogens; using live vectors expressing tumour antigens or using tumour immunogens administered in adjuvant formulations. All vaccines try to induce a potent immune response, usually involving T cells that produce the IFN-? factor ‘interferon gamma’. This factor is critical in promoting cancer elimination. Unfortunately it has been found that it is more difficult to induce a potent immune response in patients than in normal healthy donors.

IFN-g producing cells can be turned off if given a negative signal by another soluble factor that can be produced by human cells, interleukin 10 (IL-10). We have discovered that a T cell which produces IL-10 is abundant both in malaria and cancer immuno-suppressed patients. Therefore, the basic protective (IFN-g producing) cell in malaria and in cancer may be turned off by the same mechanism. Our data in a small number of patients showed IL-10 producing cells (which we call Tr1) are incredibly abundant in some breast cancer patients. These patients also have, as we would predict, deficient IFN-g production by their T cells. This year we found that this can be generalised to the majority of cancer patients, with abundant Tr1 cells found in their blood. We also found these cells appear to be ‘switched on’ continuously, which is not seen in healthy people.

Why are these cells suppressor Tr1 cells turned on? And more importantly, can we turn them off? We have collected serum from the blood of patients and controls to test for presence of suppressor factors and suppressor-inducer factors, which will provide clues to the first question. To try to target these cells for elimination, the research team has been looking at their surface characteristics. This has led to the observation of an additional suppressor cell also present in these patients. When we depleted this cell out of cultures of peripheral blood cells from patients, their cells responded much better to a cancer protein which is a currently tested as an experimental human vaccine component (mucin-1, MUC1). One way in which it is being possible to make T cells producing one factor switch to another is to stimulate them with a variant of the peptide they normally recognise. This peptide is shown to the T cells associated with molecules called MHC. We have shown this year two new ways in which peptides can associate with MHC, and consequently can predict much better how they would interact with T cell receptors to stimulate them. Based on such structural studies we are now going to design peptides which we predict would be able to powerfully stimulate T cells to produce IFN-g and not IL-10. If we are correct, such variants could then be incorporated into therapeutic vaccines.