Molecular Vaccinology Laboratory

Denise Doolan Staff
Funding
Collaborators
Student Projects
Key Recent Publications
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Lab Head: Dr Denise Doolan

Translational and Vaccine Immunology Images Malaria: The challenges for vaccine development

Despite intense research efforts, malaria remains a significant public health problem worldwide. Each year, up to three million deaths and 300-500 million episodes of clinical illness are attributed to malaria. The disease is also associated with significant constraints on economic progress and productivity especially in the developing world. With the spread of drug-resistant Plasmodium parasites and insecticide-resistant Anopheles vectors, development of an effective malaria vaccine is considered a public health priority. However, the complexity of the Plasmodium parasite and the human host pose enormous challenges for malaria vaccine development. Plasmodium falciparum has a multi-stage life cycle and a large 23 Mb genome expressing 5,268 putative proteins. Many of these proteins exhibit allelic variation between species, or antigenic polymorphism typically at sites recognized by antibody or T cell responses. To date, only a handful of the ~ 5,300 potential target antigens expressed by P. falciparum, representing less than 0.3% of the genome, have being pursued as vaccine targets. From the host perspective, malaria is a chronic infection and the Plasmodium parasite is capable of evading or modulating the host immune response. The pathogenesis and clinical manifestations of malaria are influenced by many factors, including the genetics and age of the host, the extent of exposure to the parasite, and the transmission dynamics of the parasite. A much better understanding of the interactions between the Plasmodium parasite and the human host, on the molecular level, is required. Two human models of whole organism vaccination demonstrate the feasibility of developing a malaria vaccine. Immunization with radiation-attenuated Plasmodium spp. parasites confers sterile protection against sporozoite challenge in both humans and animal models; and natural long-term exposure to the parasite is associated with an age-related decrease in the incidence, prevalence, and density of infection. The critical effector mechanism in the radiation-attenuated sporozoite model is thought to be CD8+ T-cell responses directed against parasite antigens expressed in the liver stage. In the naturally acquired immunity model, antibodies directed against blood-stage parasite antigens are thought to be responsible for protective immunity. Based on these two models, we are developing a multi-stage multi-immune response vaccine against malaria comprising antigens expressed in the liver stage and targeted by T-cell responses, as well as antigens expressed in the blood-stage and targeted by antibody responses. .

Immune mechanisms and target antigens of protective immunity

The focus of the Translational and Vaccine Immunology Laboratory is on understanding the molecular basis of immunity to malaria and identifying the antigenic targets of this immunity. One aspect of the research program uses a series of complementary cutting edge technologies that integrate the disciplines of genomics, proteomics and molecular immunology to profile the human host - Plasmodium parasite relationship on a molecular level and to identify novel antigens from genomic sequence data for diagnostic and vaccine applications. Another aspect of the research investigates neonatal immunity and the acquisition of immunity to malaria with age and exposure. The ultimate goal of this research is to facilitate the development of a vaccine against malaria, a disease that remains a major public health threat despite decades of promising research.

Staff

Labhead:	Dr Denise Doolan
Research Assistants:	Penny Groves Kathy Buttigieg

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Funding

We gratefully acknowledge support from the following organisations and funding bodies:

Pfizer Australia
The National Institutes of Health (NIH, USA)
The National Health and Medical Research Council

Collaborators

Dr Philip Felgner,
University of California Irvine, USA
Dr Pedro Alonso
Barcelona Center for International Health Research, Spain and Centro de Investigaçao em Saude da Manhiça, Mozambique
Dr Alessandro Sette
La Jolla Institute for Allergy and Immunology
Dr Kwadwo Koram
Noguchi Memorial Institute for Medical Research, Ghana
Dr Xiaowu Liang
ImmPort Therapeutics, Irvine, USA
Dr Thomas Richie
Malaria Program, Naval Medical Research Center, USA
Dr Alyssa Barry
MacFarlane Burnet Institute for Medical Research and Public Health (Burnet Institute), Melbourne

Student Projects

The Translational and Vaccine Immunology Laboratory has a number of projects available for BSc Honours and PhD students in the following areas:

understanding the molecular basis of immunity to malaria
identifying the antigenic targets of protective immunity
characterising the potential of newly identified Plasmodium antigens as target antigens for vaccine development
preclinical evaluation of novel candidate malaria vaccines based on new targets and/or new vaccine delivery systems

Key Publications

Doolan DL and Hoffman SL. 1997. Multi-gene vaccination against malaria: A multi-stage, multi-immune response approach. Parasitol Today. May. 13(5):171-78.

Doolan DL, Hoffman SL, Southwood S, Wentworth PA, Sidney J, Chesnut RW, Keogh E, Appella E, Nutman TB, Lal AA, Gordon DM, Oloo A, and Sette A. 1997. Degenerate cytotoxic T cell epitopes from P. falciparum restricted by multiple HLA-A and HLA-B supertype alleles. Immunity. Jul. 7(1):97-112.

Doolan DL, Southwood S, Chesnut R, Appella E, Gomez E, Richards A, Higashimoto YI, Maewal A, Sidney J, Gramzinski RA, Mason C, Koech D, Hoffman SL, and Sette A. 2000. HLA-DR-promiscuous T cell epitopes from Plasmodium falciparum pre-erythrocytic-stage antigens restricted by multiple HLA class II alleles. J Immunol. Jul 15. 165(2):1123-37

Wang R/ Doolan DL, Le TP, Hedstrom RC, Coonan KM, Charoenvit Y, Jones TR, Hobart P, Margalith M, Ng J, Weiss WR, Sedegah M, de Taisne C, Norman JA, and Hoffman SL. 1998. Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science. Oct 16. 282(5388):476-80.

Doolan DL and Hoffman SL. 2000. The complexity of protective immunity against liver-stage malaria. J Immunol. Aug 1. 165(3):1453-62.

Doolan DL, Southwood S, Freilich DA, Sidney J, Graber NL, Shatney L, Bebris L, Florens L, Dobaño C, Witney AA, Appella E, Hoffman SL, Yates JR 3rd, Carucci DJ, and Sette A. 2003. Identification of Plasmodium falciparum antigens by antigenic analysis of genomic and proteomic data. Proc Natl Acad Sci USA. Aug 19. 100(17):9952-57.

Doolan DL, Aguiar JC, Weiss WR, Sette A, Felgner PL, Regis DA, Quinones-Casas P, Yates JR III, Blair PL, Richie TL, Hoffman SL, and Carucci DJ. 2003. Utilization of genomic sequence information to develop malaria vaccines. J Exp Biol. Nov 1. 206(21):3789-3802.

Doolan DL and Martinez-Alier N. 2006. Immune response to pre-erythrocytic stages of malaria parasites. Curr Mol Med. Feb. 6(2):169-85.

Sundaresh S, Doolan DL, Hirst S, Mu Y, Unal B, Davies H, Felgner P, and Baldi P. 2006. Effectiveness of DNA microarray data analysis techniques for the identification of significant humoral immune responses in protein microarrays. Bioinformatics. Jul 15;22(14):1760-6.