The Johns Hopkins Malaria Research Institute

Malaria
Malaria is an ancient disease of humans that currently causes the deaths of 2-3 million people a year worldwide, mostly African children under the age of 5. A child dies from malaria every 30 seconds in developing countries. More than a third of the World's population - about 2.3 billion people - is at risk of infection from malaria, and 300-500 million individuals are infected each year. These numbers are going up, rather than down, because of increasing drug resistance of the malaria parasite and increasing insecticide resistance of the mosquito vector. Despite the magnitude of the problem, little has been invested in malaria research by the industrialized countries that fund most medical research. Resources that have been made available have been spent primarily on control programs that use existing methods, rather than on research to develop new tools for malaria control. Recent studies suggest that the number of malaria cases will double within 20 years if new methods of control are not devised and implemented.

The Johns Hopkins Malaria Research Institute
In May of 2001 the Johns Hopkins Bloomberg School of Public Health received a gift of $100 million to establish a Malaria Research Institute. The donor envisioned an investment in a broad program of basic malaria research that would result in new approaches to malaria treatment and control that would make a significant difference in combating this ancient scourge. The time is ripe for this investment because a vast amount of new data on the genome sequences of humans, the Anopheles mosquito and Plasmodium falciparum is available and new tools for effective use of this information are under rapid development.

The guiding concept of the Johns Hopkins Malaria Research Institute (JHMRI) is to focus on a program of basic science that encompasses all components of the complicated malaria life cycle - mosquito vectors, host immune responses and parasite biology, complemented by development of core facilities and bioinformatics capability. The life cycle illustration shows the diversity of approaches that Institute investigators are taking in the effort to defeat the disease.

Current Research
Treatment
Isabelle Coppens' program is focused on a little-studied area in malaria research - identifying factors in the hepatic environment that are crucial for the successful replication of Plasmodium. This line of investigation may provide new therapeutic approaches against malarial infections by blocking the nutrient uptake pathways or usurping these pathways for delivery of parasiticidal compounds. The research groups led by Gary Posner and Theresa Shapiro are developing new antimalarial drugs based on the biological and chemical mechanisms of artemisinin, a Chinese herbal remedy for malaria.

Drug resistance is a major problem in the treatment of malaria, and Ernesto Freire's laboratory is working on the development of new strategies in which drug molecules are conferred with adaptive properties that allow them to maintain efficacy in the face of naturally existing polymorphisms and mutations associated with drug resistance. To this end, they are successfully targeting the development of plasmepsin inhibitors. David Sullivan and his team are investigating how current malaria drugs like chloroquine inhibit heme crystallization to kill the parasite, and they are screening existing FDA-approved drugs for antimalarial action based on this process.

Clara Kielkopf's laboratory is focusing on understanding how RNA messages are processed using X-ray crystallographic techniques to determine the three-dimensional shapes of protein/RNA complexes. By comparing the shapes of P. falciparum with human protein/RNA complexes, they will be able to design new drug molecules that selectively affect this essential process in the malaria parasite. And Sean Prigge is focusing his research on essential metabolic pathways in the malaria parasite with the ultimate goal of designing drugs to block them and kill the parasite. He and his team are working on six enzymes that are essential to the parasite's ability to make fatty acids. Their results show how these enzymes catalyze the steps of fatty acid biosynthesis and which steps are sensitive to antibacterial drugs.

Control
Fidel Zavala's work is focused on the dual role of CD8+ T cells as anti-parasite effectors and regulators. Understanding the nature of immune response to malaria infection will facilitate vaccine development.

A major focus in Nirbhay Kumar's laboratory is investigating molecular mechanisms involved in the differentiation and development of sexual stages of the parasite leading to mosquito infection and malaria transmission with the goal of developing a transmission-blocking vaccine.

Marcelo Jacobs-Lorena's team has developed a genetically modified mosquito that is impaired for parasite transmission. They are currently investigating the molecular mechanisms by which the malaria parasite moves in the mosquito to allow transmission from one vertebrate host to another. George Dimopoulas and his group are also targeting interactions between the parasite and its vector, with a particular interest in mechanisms of the mosquito's immune system implicated in killing parasites.

Environmental control is the focus of Douglas Norris and his laboratory colleagues. The Norris group has found differential levels of insecticide resistance in mosquitoes from African villages using differing levels of agricultural insecticides. They are using molecular population genetics to investigate the structure of mosquito populations with the goal of understanding the flow of resistance to insecticides or parasite infection from one population to the next. Greg Glass is studying mosquito ecology and has established the Environmental Surveillance Core Facility, which provides data and tools with which malaria researchers can monitor environmental conditions in areas of malaria transmission.

A resource for all investigators is The Malaria Institute at Macha, a new field research station in Zambia. Coordinated by Clive Shiff, it is funded by JHMRI and operates as a collaboration between JHMRI and the Macha Malaria Research Institute. This facility, slated for completion in 2004, will provide housing and research facilities for investigators from Hopkins as well as collaborators from other institutions.

Recent Developments and Events

• The development of an in vitro method of detecting very low levels of Plasmodium, providing prompt, affordable diagnosis.
• The new GeneChip Plasmodium/Anopheles Genome Array, the first such product to provide comprehensive coverage of two organisms on a single array, was developed with JHMRI support. The chip will assist the progress of malaria research worldwide by providing investigators with a novel tool to define biochemical targets for drug and vaccine development.
• A study of pregnant women infected with HIV that showed that mother-to-child transmission of HIV is significantly increased when the mother is also infected with malaria (Brahmbhatt, et. al.).
• The Second International Malaria Research Conference was hosted by the JHMRI in March 2004, bringing together 25 speakers and 300 participants for a two-day meeting.

US Coalition News

The Communications Working Group, through support provided by The Partnership for Child Health Care, Inc., recently completed production of a new brochure entitled Basic Actions for Child Health...and a Healthy Global Future. The brochure provides an overview of the US Coalition, educates readers about interventions that can improve child health and survival, and explains the need for increased resources. Written to engage a wide audience, the brochure will be used to raise awareness among child survival advocates. To request a copy of the brochure, please contact .

On May 4th, the US Coalition participated in the poster session at The CORE Group Spring Membership Meeting in Baltimore, Maryland. The poster highlighted the goals and activities of the Coalition and encouraged organizations to join.

The Public Policy working group organized a sign-on letter and submitted written testimony to the House Foreign Operations Appropriations Subcommittee urging the committee to increase funding for child and maternal health programs to $660 million.

Every year, the rules of the U.S. Congress require that a budget resolution be approved by April 15 that outlines in broad terms priorities for the coming year. This budget includes information about funding for federal agencies as well as domestic issues. This year the Conference Committee on the budget resolution was unable to come to agreement before the spring recesses. The House and Senate have agreed on an $821 billion budget, but disagreements over tax cuts and other provisions are holding up the conference report process. Following the Memorial Day recess, Congress will begin consideration of the 13 Appropriations bills including Foreign Operations.

Membership Spotlight: Medicines for Malaria Venture

Malaria - the biggest killer of children in sub-Saharan Africa
Over one third of the world's population is at risk of malaria, a disease that kills a child every 30 seconds. Based on conservative estimates, more than one million people die each year from malaria, and many more are disabled when the parasite attacks the brain. The majority of the victims are children whose immune systems are not as developed as adults'. These tragedies can be avoided as malaria is a treatable disease, and often for less than $1. More than 90% of the deaths are preventable with effective antimalarial drugs. However, cheaper drugs, such as chloroquine that is still widely used in Africa, are largely ineffective due to drug resistance.

The need to restock the medicine cabinet
While the malaria parasite was making a quiet comeback beginning in the late 1970's, the malaria R&D pipeline went dry. During that period, only three antimalarials were developed, and they were all prophylactics designed for the military and wealthy traveler, not the rural poor. As the Department of Defense's Walter Reed Army Institute of Research observed in 2003, "it makes little commercial sense to turn out costly pharmaceuticals for people who can't afford shoes."

In late 1999, the WHO, the World Bank, foundations and representatives from the pharmaceutical industry initiated an innovative institutional mechanism to restock the malaria medicine cabinet. Structured as a public-private partnership, Medicines for Malaria Venture (MMV), a not-for-profit organization, seeks to discover, develop and deliver new antimalarial drugs as "global public goods."

Achievements
MMV currently has 36 academic and industry partners based around the world. With 11 staff, it is based in Geneva, Switzerland, home of the World Health Organization. Since its inception, MMV has received funding pledges of $98 million from various foundations, donor governments and corporations, with the largest contribution coming from the Bill & Melinda Gates Foundation.

After just four years of operation, MMV now manages the largest portfolio of malaria drug research in history with 21 projects in different developmental stages. Perhaps more important than the total number of projects is the level of genuine innovation - MMV has eight completely new therapeutic targets represented within the 11 discovery projects and 10 development projects in the pipeline. The clinical development projects are gaining momentum, and several of pre-clinical projects are set to move into clinical studies in 2004.

MMV's goal is to develop a new drug every five years with the first drug registered before 2010.

An antimalarial designed for children
One product that will most likely be available well before 2010 is a pediatric formulation of an existing antimalarial drug, Coartem. Currently, Coartem is the most effective antimalarial drug on the market. MMV is working with Novartis, a Swiss pharmaceutical company, on a pediatric form of the drug. The pediatric form will address a real and pressing need, as most of the malaria deaths in Africa occur in children under 5 years old.

Currently, the drug tablet is crushed and administered with water. However, this method is far from ideal because of the bitter taste of the drug and the difficulty in giving the correct dosage. A pediatric formulation would mask the bitter taste making it easier for children to take and make treatment more effective by improving compliance. A pivotal clinical trial of the new formulation, involving up to 700 patients, is expected to start during the third quarter of 2004. The target date for launch of the new formulation is 2007.

The pediatric form of Coartem will be provided at cost by Novartis and distributed through the WHO as part of the worldwide 'Roll Back Malaria' Partnership.

US Coalition Co-Sponsors Congressional Briefing on Reducing Malaria's Burden among Children

In commemoration of Africa Malaria Day 2004, the US Coalition for Child Survival sponsored a U.S. Congressional Briefing on April 26 on how best to reduce malaria's burden among Africa's children. The event was co-sponsored by the Global Health Council, U.S. Agency for International Development (USAID) and World Health Organization (WHO). Africa Malaria Day is observed annually throughout the world on April 25 to raise global awareness about the significant toll malaria exacts throughout Africa, particularly among children. This year's slogan, Children for Children to Roll Back Malaria, highlights the special vulnerability of children who live in malaria-endemic communities. Of the estimated 3 million deaths attributed to malaria each year, nearly two-thirds occur in children under the age of 5, most of whom live in sub-Saharan Africa.

The briefing highlighted proven, feasible, but often underutilized strategies in the fight against malaria in children. In conjunction with the event, the Global Health Council also launched its newest technical report, Reducing Malaria's Burden: Evidence of Effectiveness for Decision Makers. The program featured Allan Schapira, MD (Coordinator, Policy and Strategy Team, Roll Back Malaria Department, WHO), Martin Meremikwu, MD (Associate Professor, Department of Pediatrics, University of Calabar, Nigeria), Ok Pannenborg, MD (Senior Advisor on Health, Nutrition and Population and Head of the Malaria Team, World Bank), Anne Peterson, MD, MPH (Assistant Administrator, Bureau for Global Health, USAID), and Nils Daulaire, MD, MPH (President and CEO, Global Health Council).

Please visit www.globalhealth.org/news/article/4400 to download the presentations from the briefing or the Reducing Malaria's Burden technical report.