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Quest for a malaria vaccine: ‘The elements are in place’

16 May 2008

Tatum Anderson

Source: TropIKA

The first World Malaria day has taken place this year (25^th April) but there are likely to be several more World Malaria days before the world’s first efficacious malaria vaccine appears.

2025 is the target date for a vaccine from the PATH Malaria Vaccine Initiative (MVI) – a group of scientists, industry specialists and public health specialists that began its research after a $50 million founding grant from the Bill & Melinda Gates Foundation almost a decade ago. The lead time is so long because scientists do not yet know how to make a potent malaria vaccine say industry observers.

MVI’s director, Dr Christian Loucq agrees that there is still a mountain to climb. ‘It still is a scientific challenge,’ he says. ‘We still have a long way to go to develop the vaccine.’

Loucq, who began at MVI last year, brings more than 30 years of experience in vaccine business and global health. His aim, he says is to speed up the production of the vaccine: ‘One of the reasons I have come to the non-profit side at this time of my life, is that I have accumulated enough competencies to maybe help this part of vaccine development for the people who need it.’

In the meantime, Loucq will oversee the development of another malaria vaccine. RTS,S vaccine, a collaboration with pharmaceutical firm GlaxoSmithKline that will enter phase 3 trials at the end of the year. Although the most advanced vaccine ever developed, RTS,S is, only 35% efficacious.

For Loucq, even this vaccine will still contribute to controlling one of sub-Saharan Africa’s most deadly diseases because it will reduce the risk that an inoculated child – bitten by many mosquitoes – will go on to develop the disease.

Developing a more potent vaccine, however, is going to be a much greater challenge because the malaria parasite is so much more complicated than most other disease causing organisms.

Once it enters the body via mosquito bite, the parasite changes into several forms and each form acts in a completely different way. For instance, in the most virulent stage of its lifecycle – called the blood-stage – the malaria parasite produces proteins that stick to the surface of red blood cells, enabling the parasites to drill into the cells and start multiplying exponentially.

The parasite’s complexity means there are a massive number of potential protein targets – over 5000 so-called antigens – that might stimulate the body to produce enough antibodies to halt the progress of the disease.

The problem is scientists don’t yet know which of these targets could stimulate the best immune response. Indeed, to date less than 1 per cent of malaria’s antigens have been found.

Holding back the field yet further, are the vaccine technologies that are still being discovered and perfected.

With so many variables being developed, MVI’s portfolio beyond RTS,S, reflects a mixture of different vaccine development project approaches. Some candidates target antigens that appear at the early, so-called pre-erythrocytic stage of the life-cycle while most of the others target those at the later blood stage.

MVI’s portfolio also combines different vaccine technologies; some make use of existing effective vaccines, by hijacking those targeting the hepatitis B or measles virus. US company GenVec is investigating the adenovirus, for instance.

Such viral vaccines could be useful because they stimulate the body’s immune system for a longer time than other methods. That’s because they can replicate for up to three weeks after they enter the body, and will continually produce antigens. And some viruses, such as yellow fever, could be even more helpful in a fighting the malaria parasite because they target the liver, where the parasite settles.

And while state-of-the-art genomic vaccine technologies are obviously being considered, others with slightly older origins are also being investigated. It has been understood for decades that if the parasite can be irradiated to make it impotent – it still triggers a significant immune response in the body.

MVI is working with US-based Sanaria, a company that has actually built a facility to enable the glands of farmed mosquitoes to be milked and irradiated on a huge scale. The hope is to create the first attenuated parasitic vaccine.

However, MVI’s portfolio is not ideal. Many of the candidates are based on antigens that are already quite well known. As a result, the work being done is aimed at improving those targets by optimising the vaccine technologies and adjuvants – the catalysts that are added to vaccines to help improve immune response – says Loucq.

Certainly MVI believes that to get closer to the ultimate goal of 80% efficacy it must combine a number of these different vaccines – ideally to target several stages in the parasitic life cycle at the same time.

To produce a really potent vaccine, however, scientists need a breakthrough.

For MVI, that means finding more antigens that could stimulate a really large immune response.

To that end, MVI has begun investing in the search for new targets. Australian and US research centres have been tasked with finding more proteins in the blood stage and also, importantly, the liver stage. Loucq says these new antigens could hold the key to a more efficacious vaccine. ‘We do hope to have those proteins very soon and those proteins are going come into our portfolio,’ he says.

It’s an approach that is being looked at by others in the vaccine community although researchers are also considering other stages of the life-cycle. MVI as a portfolio consisting of eight vaccines (three in clinical development), but the entire global portfolio exceeds 30.

However, according to a report by the George Institute, published in September last year, this apparent healthy global portfolio is deceptive. It said: ‘The shape of today’s global portfolio is the unwitting product of scientific and technical gaps or deficits that have conspired to push many candidates through to the clinic where the majority fail.’

The report cited several weaknesses in the development community, many that were reflected in the Malaria Vaccine Technology Roadmap, an 11-point-plan to accelerate vaccine development created by the community in 2006; the report accused the community of patchy, uncoordinated research, wasting time by duplicating work, using inadequate tools to determine whether vaccines work (by measuring the immune response) and undertaking expensive field trials with weak candidates.

And it was suggested that public not-for-profit and academic researchers are not as brutal at weeding out weak candidates as industry.

MVI has certainly reacted to the critics. It is investing to standardize some of existing assays that measure antibody production and in March announced funding for the opening of one Human Challenge Centre – a facility in Seattle where volunteer adults can test the vaccine before they go to expensive field trials. It has halted one project with the US Army and Kenya Medical Research Institute (KEMRI), and is in the process of deciding whether to stop another with a China’s Wanxing Biopharmaceuticals.

Loucq says MVI wants to be at the centre of development, to make sure that everybody is sharing information, including antigen research. As part of that work, it meets regularly with other vaccine developers including the European malaria vaccine initiative.

How effective these new measures will be, will certainly become evident over time. Nevertheless Loucq is extremely optimistic about its pledge to deliver a potent malaria vaccine and make it affordable. ‘I do think that we have the elements in place to develop a vaccine,’ he says.

Key Questions

Briefly, what are the priority concerns of your organisation?

MVI’s mission is to accelerate the development of promising malaria vaccines and ensure their availability and accessibility in the developing world.
And, more precisely, what goals have you set?

To develop a vaccine with more than 80% efficacy by 2025, and a vaccine with partial efficacy by 2015.
What is it about your organisation's approach to these issues that distinguishes you from others in this field?

MVI is the hub, the centre of research into malaria vaccine development and collaborates with others in the field, including the European Malaria Vaccine Initiative.
What progress has been made so far?

The partial efficacy vaccine, RTS,S will go into clinical trials late 2008, early in 2009.
What are the main challenges outstanding?

To develop standardized assays, develop more efficacious vaccines from combining candidates from the existing portfolio, to find new antigens and the vaccine platforms that can be used to develop a potent vaccine.
Which other organisations will you be working with most closely?

Sanaria (for attenuated parasite production), Intercell, biotechnology company (for adjuvants), Austrialia’s WEHI (for antigen research) and Seattle Biomedical Research Institute (SBRI), (for antigen research and human challenge tests), Walter Reed Army Institute of Research (for assay standardisation); Portfolio partners include GSK Biologicals, NIH, LaTrobe University, International Centre for Genetic Engineering and Biotechnology, Monash University, GenVec.