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The parasite causing malaria, Plasmodium, was first identified in 1880. The role of mosquitoes in its spread was discovered in 1898, winning Ronald Ross the UK's first Nobel Prize. Why, then, when there are vaccines against many infectious agents, do we still lack an effective vaccine against malaria?
Vaccination is historically the most effective way to control infectious disease," says Professor Kevin Marsh, Director of the KEMRI–Wellcome Collaborative Research Programme in Kenya. "But when you talk about vaccines, people usually think about those against bacteria and viruses. Malaria is a protozoal parasite, bigger and considerably more complex than viruses. Developing a vaccine against malaria is, therefore, more similar in concept to developing one against cancer than measles."
Malaria is a parasitic disease that kills 2.7 million people across the world each year. It is caused by a single-celled parasite, Plasmodium, which is passed to humans by infected female Anopheles mosquitoes when they bite. Once in the body, Plasmodium has a complex life cycle.
"The parasite has to survive in the human until it passes to a mosquito," says Professor Chris Newbold, a malaria researcher at the University of Oxford. "It's therefore very good at evading the immune response. Natural immunity, which is very effective, doesn't destroy parasites completely – they can still grow in people who are clinically immune."
One of its key strategies is to shelter inside our own cells. "The parasite gets into human cells very quickly," says Professor Marsh. In this way, the parasite is 'hiding' from the immune system. Even then, the parasite has other tricks up its sleeve. Once inside cells, certain proteins appear on its surface. Although vaccines can be designed to 'recognise' these proteins, the parasite varies the signals on show. "Not only do different parasites have different protein coats – like humans having different eye or hair colour – but each parasite can also vary the particular signals it displays," says Professor Marsh. The immune response to the parasite is thus frustratingly complex. While the body mounts a variety of responses, it is still unclear which actually help to rid the body of the parasite. It also appears that, in malarial areas, immunity builds up through early life, as children encounter (and develop resistance to) different strains of parasite. Only by adulthood is someone more or less immune to malaria.
This complexity is a challenge to people such as Professor Adrian Hill, also at the University of Oxford, whose group is working on malaria vaccines. "You can't really use the whole malaria parasite to make a vaccine, but you still need to generate immunity to it. That means that we have to design a subunit vaccine, which is always difficult, and in this case the major problem is to induce a big enough immune response to kill the parasite."
While particular parts of the parasite used in subunit vaccines can mobilise some of our defences, it is difficult to get our full immunological artillery into action. So vaccines may stimulate antibody production, but have little impact on T cells, and antibodies on their own cannot eliminate the parasite.
But even if Plasmodium-specific T cells are generated, they do not always protect against malaria. And in many cases, the immune response is so short-lived that it would be of little practical value.
So what exactly are scientists looking for in a malaria vaccine anyway? "A vaccine should require as few doses as possible to work and has to be cheap to make and administer," says Professor Hill. The vaccine should offer long-lasting, preferably life-long, protection against all parasite strains. Although it is the blood stage that causes clinical disease, an ideal vaccine would be a combination, able to work against multiple stages.
As malaria is endemic in numerous developing countries, the vaccine would have to be stable in different temperatures and simple to administer. Ideally, vaccine use would use existing infrastructure used for infant immunisation.
Of course, as with all research, one of the main limiting factors is money. "One of the key questions is: who should pay?" says Professor Hill. Recently, G8 finance ministers met to discuss the feasibility of advance purchase commitments (APCs) as means of funding research into vaccines for malaria, HIV/AIDS and tuberculosis. APCs create a market for products aimed primarily at developing countries – a market not normally seen as commercially viable.
Public–private partnerships can also play a role. One example is the Malaria Vaccine Initiative (MVI), launched by the Program for Appropriate Technology in Health (PATH), an international nonprofit organisation. The MVI organised a 'roadmap' meeting in March 2005, to bring the scientific community together and to define goals for malaria vaccine research. "A lot less is spent on malaria, considering the scale of the problem and looking at the relative amount spent on some other diseases," argues Professor Marsh. "There's a problem too in the lack of investment in scientific capability in Africa. We need more money to carry out science in Africa, for Africa."
Despite promising leads, the key question remains – when will a cheap, effective vaccine be widely available? "People have been asking us that for the last 25 years; it's impossible to say," says Professor Newbold. "However, I think we will see something that will make a difference in ten to 20 years. As for something that's really effective, I wouldn't like to say."
Malaria vaccines in development
Pre-erythrocytic stage (sporozoite and liver stage)
Some potential vaccines induce antibodies against the sporozoite main coat protein, circumsporozoite protein – e.g. the most successful vaccine so far, RTS,S (GSK Biologicals).
Others induce T-cell response – e.g. DNA or viral vector vaccines that encode pre-erythrocytic antigens recognised by T cells (Oxford).
All vaccines in progress induce antibody responses. There are many potential targets, on or released by the merozoites as they attach to red blood cells. Many vaccines focus on MSP-1 (merozoite surface protein-1). Other targets include MSP-2, -3, -4 and -5, AMA-1, and GLURP.
Vaccines that produce antibodies to malarial targets on the red blood cells are much less developed than those targeting the merozoites.
T-cell-based vaccines for the blood stage remain theoretical.
Vaccines for these stages would block disease transmission. The vaccines in development mostly induce antibodies that the mosquito takes up when it bites, and block parasite development in the insect's stomach – e.g. Pfs25 (US National Institute of Allergy and Infectious Diseases).
These will not prevent disease in an individual but would affect disease in the population.
These are carried out using vaccines against several stages.
Chrissie Giles is a freelance writer based in London.