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Malaria vaccines: Renewed promise

Filip Dubovsky only treated a single case of malaria while working as a pediatrician in California, and his diagnosis of this case was entirely unexpected. While treating a young patient with appendicitis, he also noticed the telltale signs of malaria. Several years after this brief encounter with the parasitic disease, Dubovsky is the scientific director for a US-based nonprofit organization that is devoted to the development of a vaccine to help end the scourge of malaria in developing countries. Malaria, along with tuberculosis and HIV/AIDS, is among the most deadly communicable diseases, killing nearly 3 million people each year. The Malaria Vaccine Initiative (MVI), a division of PATH (Program for Appropriate Technology in Health) in Seattle where Dubovsky works, is trying to accelerate the discovery process for an effective malaria vaccine and the field may soon reap the benefits.

"This is the golden age for malaria vaccine research and we are going to see a lot of data coming in over the next few years," says Dubovsky. "We now have real proof that a malaria vaccine is possible and that it can save the lives of children in Africa."

This new evidence was a long time in coming. Vaccinologists and parasitologists have been trying for decades to develop a vaccine for malaria. But there were many scientific obstacles to overcome first, not the least of which was decoding the sequence of more than 5,000 genes that make up the Plasmodium falciparum—the most lethal of the malaria parasites. After this was accomplished three years ago, the pace of vaccine research gathered speed. "The science is here, and finally the biotechnology is at a point where we can develop promising candidates," adds Dubovksy.

There are now dozens of promising malaria vaccine candidates in various stages of clinical development. There are two main ways these experimental vaccines can help control malaria. There is a critical turning point in the parasite's development once it enters humans. Vaccines that act before this point would offer sterilizing protective immunity, because they would prevent immunized individuals from developing an established malaria infection. Other vaccines that act after this point would work by limiting the severity of disease. Scientists are currently faced with a similar situation in the pursuit of an AIDS vaccine.

The malaria vaccine candidates that are the furthest along in development work by the second route and do not offer complete sterilizing immunity. This type of vaccine could still make great strides in reducing the mortality associated with malaria and could have immense social and economic benefits in the hardest hit areas. In countries where malaria is widespread, the parasite is responsible for up to one quarter of all deaths in children under the age of five. Malaria's burden falls primarily on the younger generations that would eventually become important contributors to the welfare of both their household and community. Malaria is also increasingly linked with other diseases like AIDS. Children and women, particularly pregnant women that are HIV infected, are disproportionately affected by malaria and in many African countries the diseases overlap geographically. In people who are co-infected, both diseases can progress more rapidly and this can have grave implications.

Meanwhile researchers are continuing the search for vaccine candidates that could provide sterilizing protective immunity. "We have several candidates going forward now, and we've already eliminated a lot that don't work. All this is great news," says Dubovsky. However the ultimate challenge for the malaria vaccine field will come once a successful candidate progresses through clinical trials. Then the test will be getting the vaccine to those who need it most.

From mosquito to human

A malaria infection occurs when a female mosquito bites a human. In the process, the mosquito transmits parasites into the blood. At this point, the parasite is in an early stage of maturity known as a sporozoite. Once inside a human, the parasite goes through a complex growth process. To reach the next stage the sporozoites must make the journey to the liver, where they use liver cells to reproduce. This is the critical turning point where an established infection occurs. A sterilizing vaccine would stop the parasite before reaching the liver. To do this successfully it must block all of the parasites because even if just one sporozoite finds its way to the liver, it can rapidly multiply and still cause a lethal infection.

After replicating in the liver, the parasite is then released into the blood. This stage of the parasite is called a merozoite. The merozoite then enters red blood cells where it can produce even more parasites. Once huge numbers of parasites form it causes the red blood cells to rupture resulting in shock, severe anemia, coma, and eventually death. A vaccine that acts after the parasite reaches the liver would hinder reproduction so that fewer parasites make it into the blood. This type of vaccine would reduce the severity of disease and lessen the likelihood of death. Researchers refer to a vaccine that does not offer sterilizing immunity as "leaky" because it allows some of the parasites to leak through the immune response. Designing this type of vaccine is now proving a simpler task than one that induces sterilizing immunity.

Although a leaky vaccine is not 100% effective it will allow children to slowly develop natural immunity to the parasite. In areas where malaria is prevalent, people are repeatedly bitten by infected mosquitoes and are continuously exposed to the parasites. This allows them to build up some immunity against malaria so that even though parasites are entering the liver, the immune system is controlling their numbers. By the time people reach adulthood, many of them have developed enough immunity to avoid severe symptoms and death. Children and infants are therefore at the highest risk for severe malaria and death, and 90% of severe disease occurs between the ages of 5 months and 3 years.

In the absence of a vaccine other simple interventions are effective at lowering rates of malaria infections. By reducing the number of mosquito bites, insecticide-treated bed nets can reduce the number of infections by 45% in areas where they are used regularly and properly. But as is often the case, the simplest interventions are often unavailable or not widely accepted.

There are also anti-malarial drugs that can be taken as prophylaxis before exposure to the parasite, but unfortunately these are of little use in developing countries because of increasing drug resistance in the parasite in many endemic areas. One popular anti-malarial to which there are now high levels of resistance is chloroquine. Newer and improved strategies for treating malaria involve taking combinations of drugs, as is the strategy with HIV infection. Like antiretrovirals, combination therapies for malaria also have high price tags and are not available in all areas, making them only feasible as treatments where the risk of disease is very high. The World Health Organization (WHO) just recently adopted these updated regimens for use in its Roll Back Malaria program after being criticized by researchers and activists for treating people with outdated and sub-optimal malaria therapies.

Progress in trials

Several malaria vaccine trials are currently ongoing in Africa with a robust array of candidates. There are four candidates in trials that aim to provide sterilizing immunity with an additional nine in earlier development. The selection of candidates that may limit severity of disease is even more expansive. Nine candidates are now in clinical trials and another 28 are still in the laboratory.

The field's lead candidate was developed by the pharmaceutical company GlaxoSmithKline (GSK) and is now being readied for a large-scale efficacy trial (Phase III) in approximately 13,000 children at 6 to 8 sites throughout Africa. This vaccine candidate, known as RTS,S, seems to limit disease progression and prevent childhood deaths. GSK started malaria vaccine research in 1984 and just recently completed a Phase IIb trial in Mozambique that enrolled more than 2,000 children. Completion of this trial was a landmark in malaria research, according to Regina Rabinovich, the director of infectious diseases at the Bill & Melinda Gates Foundation.

The vaccine was 57% effective at preventing severe malaria through six months. The RTS,S candidate is composed of a single protein from the surface of the sporozoite attached to a hepatitis B virus protein and is delivered with an adjuvant known as AS02. The vaccine cannot cause malaria or hepatitis B and caused few side effects in the Phase IIb trial. Preparations for the Phase III trial are now underway and the company is spending millions of dollars on refurbishing an existing manufacturing facility to produce the vaccine for the trial, according to Ripley Ballou, vice president of emerging disease at GSK. The company is also investigating the optimal dosing strategy for the trial. Ballou predicts that a prime vaccination followed by a booster shot will likely give the best response.

Many other research groups are currently investigating ways to include other parasite proteins in a vaccine candidate to find one that induces sterilizing immun-ity. Stephan Kappe of the Seattle Biomedical Research Institute in the US is researching which of the parasite's 5,000 genes are required for it to establish infection in the liver. Many of the vaccines now in development have relied on the same handful of proteins to induce an immune response to the parasite. Kappe's work is intriguing to many in the field who think additional proteins will need to be included in a vaccine for it to be completely effective at stopping the parasite.

Ensuring access

Although activity and funding in the search for a malaria vaccine has been increasing steadily, much of this work has been accomplished with a strikingly small budget. Dubovsky estimates that only US$27 million this year will be spent on malaria vaccines. The partnerships between private companies like GSK and non-governmental organizations like MVI have helped keep malaria vaccine research on the agenda. Industry is reluctant to invest in research for products like malaria vaccines that would not be sold in the lucrative US or European markets. Drug prophylaxis is sufficient and available to travelers from areas where malaria is not prevalent to protect them from getting malaria. "For products like this, there needs to be some promise that someone is going to buy the vaccine in order for industry to make such a large commitment," says Ballou.

Discussions about potential strategies for making a malaria vaccine available at an affordable price are now being held between industry and organizations like the Gates Foundation and MVI. Similar planning and discussions are taking place around AIDS vaccines and many in that field are looking at malaria vaccines as a model.

"A vaccine can be licensed, but until someone steps up and says they are going to buy it for their country and start massive immunization campaigns, it doesn't matter much," warns Ballou. "You can give the vaccine away for free, and there's still a cost involved."

To this end, MVI is planning to get a licensed malaria vaccine included in the WHO's Expanded Programme on Immunization in developing countries. "It's the best system we have and our goal is to get an effective malaria vaccine integrated into it," says Dubovsky.

In a recent speech at the Brookings Institution (a US-based public policy think-tank) Nelson Mandela reminded policymakers that African countries need improved access to treatment and prevention resources for the three biggest killers: AIDS, malaria, and tuberculosis. "Freedom, after all, means nothing to someone left to die at the mercy of these preventable and treatable diseases."