Contagious success

Australians lead the way in vaccine research for malaria and other infectious diseases, writes Michael Good.

About one third of the 50 million deaths that occur each year are caused by infectious diseases, making pathogenic organisms the world's number one killer. In Australia, our contribution to infectious diseases research has been disproportionate to our small size. Early work of Joseph Bancroft, Howard Florey, Macfarlane Burnet, Neil Hamilton-Fairley, Frank Fenner and Ralph Doherty, to name but a few, has inspired following Australian generations to continue the noble quest to understand the pathogenesis of these diseases and to develop vaccines and therapies.

One of the most challenging problems of our time has been malaria. One to two million children die every year from malaria and this disease has also had a dramatic impact on economic development, and consequently the prevalence of other diseases, in affected countries.

Australia has a proud history of research in malaria. Neil Hamilton Fairley and his group of army malaria researchers in Cairns demonstrated during the Second World War years that regular atebrin use was an effective anti-malarial agent. He also made the very significant observation that following the bite of an infectious mosquito, the parasite could be found in the blood for only a very short period of time but then reappeared after about one week. It was subsequently shown that the parasite was resident in the liver for this period. These experiments were performed using volunteers who received blood taken from other volunteers on whom malaria-infected mosquitoes had been fed at various preceding times. This early work was critical to unravelling the life cycle of the parasite and so ultimately establishing rational vaccine strategies.

Malaria vaccine approaches

Vaccine strategies were boosted when, 22 years ago, scientists at The Walter and Eliza Hall Institute of Medical Research (Kemp D et al, PNAS 1983) and at New York University (Ellis J et al, Nature 1983) were the first to clone malaria antigens, giving hope that a vaccine based on recombinant subunits of the parasite might be around the corner. Their research laid the groundwork for vaccine programs aimed at stopping the parasite in the blood or in the liver.

An Australian, Richard Carter, who was working at NIH at that time, demonstrated that the stage of the parasite found in the mosquito could also be targeted by vaccine approaches. This research is now being developed towards vaccine production by Australian Allan Saul, co-director of the Malaria Vaccine Development Unit at NIH.

In the mid-1980s, Louis Schofield (New York University), myself (NIH) and colleagues demonstrated that cell-mediated immunity was critical to vaccine-induced protection at the sporozoite/liver stage in the life cycle. However, vaccine research performed in Australia has focussed primarily on the blood stage of the life cycle and in 2002, the results of the first vaccine trial using recombinant blood stage malaria proteins (a mixture of three recombinant fragments referred to as 'Combination B', undertaken in Papua New Guinea) were published. This promising trial, which demonstrated up to 60 per cent efficacy, was a collaborative research effort between PNG, Australian and Swiss researchers.

Other recombinant vaccines being championed by Australians include AMA1 and MSP2 (Robin Anders), MSP1 (Brendan Crabb), MSP4/5 (Ross Coppel) and RAP2 (Allan Saul and Michael Hocart).

In 1995, researchers cloned an elusive protein expressed on the surface of infected red cells. The protein, referred to as PfEMP1, plays a critical role in malaria pathogenesis and is known to switch expression within one clone of parasite to facilitate immune evasion.

Australian scientist Russell Howard, at Affymax, led one of the successful cloning teams. This work has had an enormous impact on understanding the parasite's ability to evade immunity and is also leading towards a molecular understanding of 'pregnancy-associated malaria' where there is limited expression of variant forms.

Graham Brown (University of Melbourne) and colleagues have identified placental receptors for PfEMP1, and this work holds important implications for development of specific therapeutics and vaccines to prevent pregnancy-associated malaria.

Other approaches are also being followed here and overseas, including the strategy of directly targeting those factors responsible for disease symptoms as opposed to the parasite per se (Louis Schofield, Ian Clark). The Australian company, Saramane, and subsequently The CRC for Vaccine Technology, played a coordinating role in many of these vaccine programs.

DNA-based malaria vaccines

Today, we are undoubtedly closer to that vaccine, but it still remains elusive. The major challenge with malaria vaccine development has always been the polymorphic nature of the parasite and its ability to evade immune responses. Will it, in fact, be possible to develop an effective vaccine using one or a few recombinant fragments known to be polymorphic in the parasite? This question, which remains unanswered after 20 years, has led others to pursue more traditional vaccine strategies. Thus, the approach being followed recently by Steve Hoffman and colleagues at Sanaria in Rockville, MD, has been to develop a vaccine using radiation-attenuated sporozoites. Hoffman believes that the logistical problems associated with developing and storing frozen parasites for worldwide use can be overcome.

While this research is being received with caution by the malaria research community, Hoffman has on his side the fact that irradiated sporozoites can induce complete protection in volunteers. Australian scientist Denise Doolan has been working with Hoffman for many years using this radiation-attenuated model to understand the mechanism of immunity in volunteers and to mimic this type of immunity using DNA-based vaccines.

We are following a related strategy at the Queensland Institute of Medical Research, and have demonstrated that exposure of mice and human volunteers to whole blood stage parasites in exceptionally low doses can induce potent and protective cell-mediated immune responses that target highly conserved antigens. Our results support work performed by Chris Parish (John Curtin School of Medical Research) more than 30 years ago, which showed that antigen dose was critical to the type of immune response induced.

We observe that the lower the dose of parasite antigens, the higher the cell-mediated immune response. Because low doses of antigen are essential, logistical problems in growing parasites and preparing sufficient antigen for large-scale vaccination should not be an impediment.

Funding future malaria research

A major non scientific challenge for malaria research in both Australia and overseas has been to source sufficient funding for basic research, developmental research and clinical trials. Although the Gates Foundation, through the Malaria Vaccine Initiative, is providing much needed funding, it has been estimated that 10 times as much funding is required if a vaccine is to be developed within the next 10 years. However, chance does favour the prepared mind and in Australia our per capita population of dedicated malaria researchers with prepared minds, if not adequate resources, probably exceeds that in any other country.

Vaccine approaches for Streptococci

While malaria is a high-profile disease, some other diseases, responsible for almost similar amounts of suffering, are not. It has been estimated that the range of diseases caused by group A streptococci are responsible for more than 500,000 deaths per annum, a number that is almost certainly a significant underestimation (J Carapetis et al, personal communication). For some unfathomable reason, these diseases are ignored by WHO even though they exert their greatest suffering in poor countries.

While anything but a poor country overall, in Australia our indigenous populations are impoverished and suffer the highest incidence and prevalence rates of the post streptococcal diseases, rheumatic fever and rheumatic heart disease, worldwide. Socio-economic factors play the major causative role here.

However, Australian researchers, with funding from NIH, NHMRC, the National Heart Foundation, the Prince Charles Hospital Foundation and the CRC for Vaccine Technology, are testing a novel vaccine approach based on a highly conserved peptide found on the surface M protein of all strains so far tested from all continents. If successful, this vaccine will have a dramatic effect on cardiovascular health in all countries. A competing technology based on the amalgamation of 26 peptide determinants representing the most common strains prevalent in the USA is also undergoing clinical trials.

The Australian vaccine approach has brought together researchers from the Queensland Institute of Medical Research, the Menzies School of Health Research, the University of Melbourne, the University of Queensland, and more recently the Fiji School of Medicine. With a significant funding boost from NIH, researchers are now commencing GMP manufacture for a Phase I trial in Brisbane.

A global effort

Australian researchers are also at the forefront to develop vaccines for many other diseases, perhaps most notably HPV (Ian Frazer), but also HIV, tuberculosis, leishmaniasis, schistosomiasis and influenza, and have developed very successful public health control programs to eliminate dengue, led by Brian Kay and recently published as a major article in The Lancet.

Because infectious diseases are not the number one killer in Australia, the public's health concerns are largely focussed elsewhere. However, SARS, bird flu, dengue and malaria have all received considerable media coverage and serve to remind us that, although Australia is an island, we are at the ebb and flow of all of the world's major killers. As a generous nation, we also take pride in the fact that our research, our effort, is making a very significant contribution to the health of disadvantaged people throughout the world.

Prof Michael F Good is director of The Queensland Institute of Medical Research.