TARGETING A GLOBAL DISEASE


Tulane researchers use different approaches toward eliminating the same disease

By Madeline Vann
Photos by Paula Burch-Celentano

Eradicating malaria is an ambitious goal, but Tulane University School of Public Health and Tropical Medicine experts are doing their part to achieve it with a multi-disciplinary approach to prevention and treatment.

Nirbhay Kumar, professor and chair of the Department of Tropical Medicine, is working on a vaccine to block transmission of the disease while former chair and molecular geneticist Donald Krogstad is launching the NIH-funded International Center of Excellence in Malaria Research for West and Central Africa, where he will build a foundation for data collection and malaria prevention.

Their work is needed.

Last year was intended to mark a milestone for malaria prevention. The World Health Organization had set a target of cutting malaria infections in half by 2010. While significant progress has been made towards that goal, more needs to be done. Approximately 800,000 people die every year (most under age 5) from malaria, and the global cost of malaria efforts runs about $5 billion U.S. dollars, according to the 2010 World Malaria Report.

Vaccine Development

Transmission-blocking vaccines stop the process during the sexual stage of the parasite life cycle (see the gray area of the diagram). Photo credit: PATH MVI.

In combating disease, public health usually takes three approaches: preventing infection by controlling its spread, treating people who are already infected, and exploring options to vaccinate against future infection.

With malaria, preventing infection is usually achieved through the use of bed nets, pesticides, and water management practices, while treatment involves the use of antimalarial medications. Kumar, an internationally known molecular parasitologist and immunologist, has been focusing on the third approach by developing a vaccine to prevent transmission.

Malaria is caused by a microscopic parasite – Plasmodium – transmitted to humans by female mosquitoes. When a mosquito bites an individual, the parasite enters the blood stream to reside in the liver and then develop within circulating red blood cells. When other mosquitoes bite the individual, they pick up the parasites from the blood and can transmit it to someone else.

Nirbhay Kumar removes vials of malaria parasites preserved in liquid nitrogen for further culture work.

Kumar’s transmission-blocking vaccine would work by triggering an immune response in people to produce antibodies.  The antibodies would target a specific protein the malaria parasite needs in order to reproduce within a mosquito host.  So, when a mosquito picks up the parasite during a blood meal, the next stage of the cycle would be halted. With the reproduction protein out of commission, the mosquito host is effectively prevented from passing malaria on to the next human in the chain.

This process relies on a protein known as Pfs48/45, which was isolated by Kumar and his team.  Previous efforts to develop a transmission-blocking vaccine have been thwarted by the difficulty in recreating the protein in a lab.  Kumar and his associates and collaborators believe they have solved these problems, and have had success in significantly reducing transmission in studies using rodents and baboons as models for vaccination.

“When you look at the malaria transmission process, all three – parasites, people, and mosquitoes – are equally important,” explains Kumar. “We are hoping to stop the malaria infection and transmission process completely at the community level.”

Kumar’s work recently received support from the PATH Malaria Vaccine Initiative. Under the project, his team will work with Gennova Biopharmaceuticals Ltd, based in India, to develop and test the vaccine.

“Once you find the antigen, you can produce and formulate those antigens for a vaccine,” he explains. In rodent studies, the candidate antigen has shown very high efficacy in preventing transmission. Results from these studies suggest that Kumar’s team could produce a vaccine candidate that is more effective than leading competitors. Benefits to this strategy include preventing the creation of malaria strains resistant to commonly used treatments. A transmission-blocking vaccine also promises to prevent malaria from returning to regions where it has been eliminated.

Kumar estimates that with luck and a lot of hard work, within three years they could be ready to begin Phase I clinical trials in a naïve population (a group that has not been exposed to malaria).  Such as volunteer public health students at Tulane, he jokes.

Kumar began this research while a professor in the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health. While at Johns Hopkins, his team and collaborators at the Walter Reed Army Institute of Research and Kenya’s Institute of Primate Research published a study demonstrating the successful production of a purified form of the recombinant protein. Their tests concluded that it generated “potent malaria transmission-blocking antibodies” when used to immunize mice and baboons.

He moved to Tulane in January 2010 as professor and chair of the Department of Tropical Medicine to continue and also build on his research. Kumar has a vision for comprehensive malaria prevention research, which will be reflected in the make-up of the department.  This vision calls for hiring additional faculty with expertise in all areas of malaria prevention and adding to the broad expertise already resident in the department.

“Total elimination is a lofty goal,” he says. “I think gradual elimination is possible to a point where malaria can be effectively controlled with drugs, bed nets and even insecticides.”

Building a Center of Excellence

Donald Krogstad is launching an International Center of Excellence in Malaria Research for West and Central Africa.

Kumar joined a faculty team with a long history of working directly on the problem of malaria. Krogstad and colleagues in the department have been developing and testing a potential antimalarial medication.

The compound has successfully completed the phase I studies, which focused on safety, and will soon be moving into human clinical trials in Mali, says Krogstad.

“The investigational compound has similar side effects to chloroquine and similar pharmacology,” he says.

Krogstad’s research over 20 years in Mali combined with the proven ability of Tulane faculty to work effectively with partners in developing countries provided the foundation an award of $11.2 million over seven years from the National Institute of Allergy and Infectious Diseases, a division of the National Institutes of Health. The grant funds the establishment of a center of excellence, the goal of which is a multidisciplinary strategy to control and potentially eliminate malaria in West and Central Africa.

“We also bring a track record in training of host country investigators, which is one of the major goals of this funding and one of the reasons why it was planned for seven years instead of three — it’s hard to train somebody and get them back in the three-year time frame,” says Krogstad. He explains that the funding cannot go so far as to dictate ministry of health policy, but building capacity to carry out malaria prevention campaigns and assess their effectiveness is crucial to reaching the international goals of cutting infection rates in half and, ultimately, eliminating malaria.

The seven-year project will involve 53 investigators from partner institutions from around the world, including Tulane faculty Joseph Keating, assistant professor of international health and development; Thomas P. Eisele, assistant professor, international health and development; and Frances J. Mather, adjunct associate professor, biostatistics.  Partnering institutions include the Harvard School of Public Health, the Broad Institute, the London School of Hygiene and Tropical Medicine, Medical Research Council Laboratories (Fajara, The Gambia), University Cheikh Anta Diop (Dakar, Senegal) and the University of Bamako (Bamako, Mali).

Krogstad explains that the centers, 10 of which were funded worldwide, represent a sea-change in the way NIH views malaria research. This more comprehensive strategy is consistent with the approach of other funders like the Gates Foundation but may also be a response to increasing drug resistance in malaria strains, the presence of ineffective counterfeit drugs on the black-market in some countries, and the question of whether preventive tools, such as pesticide-soaked bed nets, will work as proposed.

Krogstad recently returned from the initial meeting of the investigators in Dakar, where the team identified their guiding priorities.

“We want to focus on the epidemiology of malaria and its vectors, immunology and pathogenesis of malaria, and resistance in both antimalarial drugs and insecticides,” he says. One of the crucial first steps is to try to get good baseline data, to create a picture of malaria in the community, in order to assess the effectiveness of interventions.

“To be really certain about what is going on, you need solid population-based data, prospectively over time, and at the moment we simply do not have that,” he says. “So our mandate in year one is to be sure above all else that we have a reasonably solid baseline so that for interventions in year two and beyond, we have something with which to compare and will have a valid comparison. It sounds frighteningly simple but is a big part of the challenge.”

As the work unfolds for both Kumar and Krogstad, the tiny mosquito that carries malaria will go about its business.  These researchers, however, have placed a bull’s eye on the Plasmodium parasite and will continue their work toward elimination – or even eradication – of the disease it carries.

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About Tulane University SPHTM

Tulane's School of Public Health and Tropical Medicine is the oldest school of public health in the country and the only American school of tropical medicine. Our mission is to advance public health knowledge, promote health and well-being, and prevent disease, disability, and premature mortality. This is accomplished through academic excellence in education of public health professionals, rigorous scientific research of public health problems, creative partnerships to advance the practice of public health, and innovative service to the local, national, and international public health community.
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