Biotech for the rest of the world

The latest medical technology is all very well - if you can afford it. Susan Williamson looks at how one Australian group is coming up with practical healthcare solutions for the developing world.

Cutting-edge research in gene therapies or organ transplantation may be applicable in developed countries like Australia, but these sorts of technologies are not useful to people in resource-poor countries who suffer from HIV, malaria, tuberculosis, or measles -- the top four health issues in the world.

But the application of Australian biotech in developing countries is inextricably linked to balancing low-tech work with high-tech -- and an eye on the bottom line.

The MacFarlane Burnet Institute for Medical Research and Public Health in Melbourne, a registered non-government organisation that works with AusAID, provides a link between the research lab and public health outcomes in developing countries throughout the Asia-Pacific as well as Africa.

"The theme or vision for the Burnet Institute is to try to look at cutting-edge good quality fundamental research and whether it is going to help in resource-poor countries and help with 90 per cent of the world's health problems," says director of the MacFarlane Burnet Institute for Medical Research and Public Health, Prof Steve Wesselingh.

High-tech meets low-tech

Half of the people employed at the Burnet Institute do not work in the lab -- they work on field programs. Most of this work occurs outside Australia in the Asia-Pacific region, in countries like Papua New Guinea (PNG), Indonesia, Cambodia, Laos and Myanmar.

This involves so-called 'low-end' or 'low-tech' capacities that are applicable in these countries, such as prevention programs and education, for example advocating the use of condoms to prevent HIV.

Countries in the Pacific region currently have low rates of HIV -- PNG has about a 1 per cent infection rate. But STD infection rates are about 30 per cent, so the potential for HIV to spread exists.

The Burnet collaborates with the PNG Institute of Medical Research, through which these figures are collated -- Wesselingh says there is a need to intervene and prevent HIV from taking off.

"The good thing about the work at the Burnet is that the field programs keep us in touch with the reality of what can be used in developing countries," says deputy director, Assoc Prof David Anderson, who has been with the Burnet for 20 years. "Often there are no good labs, no electricity, no clean water, so you need to develop things that can sit on the shelf and last, and not require training to be used."

The Burnet provides an important link between high- and low-end capacities and bringing these to developing countries.

Determining the impact of HIV in countries like PNG, for example, is not as simple as measuring viral load with PCR or CD4 counts with flow cytometry, as happens in Australia and other developed countries. Not only are these techniques expensive, their use is not appropriate in countries like PNG.

Another Burnet researcher, Prof Suzanne Crowe, is currently training people in PNG to use more appropriate technologies, such as enumerating CD4 cells down a microscope -- the cells are fluorescently labelled and instead of being passed through a flow cytometer they are visualised down a microscope.

Although not as accurate as flow cytometry, this technique is still sensitive and specific enough to obtain useful results, and is much more appropriate and applicable in PNG.

Edible vaccines

The measles virus is a major problem in PNG. An ongoing epidemic of the disease causes the deaths of many young children, particularly those who are malnourished.

"A lot of children are infected with this virus and a lot of children are not immunised," says Wesselingh. "Our role is to build capacity to give vaccines. We are developing cold chains to keep the vaccine cold; because the measles vaccine is a live attenuated vaccine it requires refrigeration to ensure it remains viable.

"We are also evaluating whether children are getting the vaccine, whether the vaccine is still viable by the time it is being injected into children, and whether they are producing antibodies or seroconverting."

Administering a vaccine by injection requires skilled staff, needles and syringes, and safe disposal facilities -- resources that are not readily available in developing countries like PNG. The Burnet is looking at alternative ways of delivering vaccines.

"To maintain and sustain global vaccine coverage you need simple cheap measures, which means an oral vaccine that is heat stable," says Wesselingh.

This work is being done at the Burnet's Melbourne labs, and involves inserting part of the measles virus into plants, such as lettuce, growing up the engineered plants, then freeze drying them to produce a powder that can be made into tablets. The engineered lettuce plants express the measles proteins, and when ingested generate an immune response against the disease.

So far, this research has shown that fresh and freeze-dried lettuce containing the measles virus generates an immune response in the lab and in mice. The research still has some way to go, but these plant-made oral vaccines have the potential to provide a safe, cheap, and easy way of distributing an alternative to the current injectable measles vaccine.

Wesselingh says the Burnet also has plans to develop oral plant-derived vaccines to give to chickens to combat the influenza virus.

Microbicides

The development of new drugs, drug targets and drug delivery is another area of research in which the Burnet is involved -- targeting health issue of major concern such as HIV, malaria, TB and measles. "It is a slow process, developing new drugs," says Wesselingh. "We are working in this area and we would work with big pharma if that's where they direct their energies."

He adds that the reason work on influenza has taken off is because of the interest by rich countries such as Australia and the US.

"We are also focusing on prevention of transmission -- HIV, for example. We are part of a collaboration with [Melbourne-based biotech company] Starpharma and the National HIV Centre in Sydney, developing the vaginal microbicide VivaGel."

VivaGel is a gel-like lubricant that women can use as a preventative strategy for protecting the vaginal lumen against infection with HIV and other STDs, such as genital herpes and chlamydia.

This product grew out of Starpharma's dendrimer technology -- the active component of the microbicide is a specifically designed dendrimer or synthetic molecule that prevents the HIV virus from binding to the vaginal epithelium. The collaboration is supported by a US$20 million NIH grant.

With their expertise in viral research, Burnet scientists have also been involved in screening second generation microbicides developed by Starpharma for anti-HIV activity, as well as determining the mechanism of any antiviral activity once detected.

"It is an opportunity to help prevent HIV, a cheap way of preventing the disease," says Wesselingh. "It also empowers women as they can have problems getting their husbands to use condoms so it empowers them to protect themselves."

The Burnet also offers public health experience in the field to this collaboration. Dr [CHECK?] Wendy Holmes, an international physician at the Burnet, is working with women and the application of VivaGel. Wesselingh says women in Sri Lanka India and Indonesia have been receptive to the idea.

VivaGel recently completed phase I safety trials and is currently in phase II trials. "Things are moving towards efficacy trials in women. It works in monkeys, test tubes and it is safe in women, so it is looking promising," says Wesselingh, adding that the Burnet has a couple of other microbicide ideas in the lab.

Select spin-out

Burnet deputy director David Anderson helped to set up a spin-out company, Select Vaccines, with a small private investment bank about two years ago. The company has had a couple of capital raising initiatives since its initial public offering, and currently has three commercial deals out of four products.

It has licensed a point-of-care diagnostic for hepatitis E, developed in Anderson's lab, with Singapore-based partner Genelabs Diagnostics (now known as MP Biomedicals after being taken over by the US company). A similar point-of-care diagnostic for hepatitis A has now been licensed to a US company for sale world-wide.

Select also has a laboratory-based test for hepatitis E, and a set of hepatitis E monoclonal antibodies, that it has licensed to Chemicon. "The monoclonal antibodies are for research use," Anderson says. "There's not a lot of dollars in them, but at least they are out there on the market."

The rapid point-of-care diagnostics are rapid immunochromatographic tests where a drop of blood, usually obtained from a finger prick, is put onto a card to which saline is added giving a result in five minutes. Quick diagnosis of infection is advantageous so as to control its spread.

"We are now able to provide this point-of-care test to the WHO for use in refugee camps in Sudan and Chad where there is a large ongoing hepatitis E problem," says Anderson. "It was also distributed after the tsunami in Asia at the end of last year."

Hepatitis E is not found in Australia, but is prevalent in developing countries like Africa and Indonesia. It is a water-borne disease that infects the gut and once it is introduced it is difficult to contain as it is transmitted by contaminated water, and is easily transmitted by person to person contact where hygiene is poor.

Prior to the test being available in Africa blood samples were sent to Egypt for testing and came back a week later, by which time the disease would have spread throughout an entire refugee camp.

"We needed a partner to take the hepatitis E test all the way through to manufacture and distribution," Anderson says. "We put many years into researching hepatitis and developing the reagents and getting the test to work, but the economies of scale for distribution of the test are an absolute killer.

"We could have taken it to being sold, but we couldn't justify selling the test in those countries, the cost of the test is low but the overheads are huge. Genelabs had distribution networks already set up in the region and an important part of the strategy is to recognise this -- to develop the test then partner for the manufacture and distribution."

Like the hepatitis E point-of-care diagnostic, the hepatitis A test will allow doctors and health workers to rapidly diagnose hepatitis A virus infection without the need for laboratory facilities.

Anderson says tens of millions of cases of hepatitis A occur around the world each year, in developed and developing countries.

"We employ differential pricing. For example, the general rule of thumb for developing countries is US$2 per test is a reasonable price. This is clearly beyond the reach of many individuals but can be used by health authorities, whereas in developed countries we would charge US$20 or $30."

Anderson says Select Vaccines is now shifting focus from the point-of-care diagnostics to vaccines.

The company has a platform technology that involves the production of virus-like particles into which surface antigens of interest, such as envelope proteins from the hepatitis C or HIV virus, can be inserted.

Anderson says this technology looks promising for a malaria vaccine construct, a HIV vaccine construct, and they are just embarking on an influenza construct.

"We have a vaccine in the pipeline for hepatitis C," he says. "We have got very good responses in small animals with one small dose of this vaccine -- a small dose of one microgram gave good immunity in mice." Anderson says Select plans to ramp up efforts on the vaccine work in the next couple of years. "It's about keeping an eye on the public health and public good, but you need to be quite hard-nosed and commercial about it and at the same time develop technology that can be easily used."