eBriefing

Progress against Malaria: Developments on the Horizon

Progress against Malaria
Reported by
Marilynn Larkin

Posted January 18, 2008

Presented By

Overview

Malaria is the leading cause of mortality and morbidity in the world, causing 300 to 500 million infections annually and between 1 and 3 million deaths, mostly among children. Every 30 seconds a child dies of malaria—that's 2000 lives lost per day.

Ninety percent of malaria's victims live in Africa, where the disease spawned by P. falciparum accounts for about one in five of all childhood deaths (Rugemalila et al, 2006). The fact that malaria continues to exact a terrible toll in less developed nations despite near eradication in developed countries provided the impetus for the creation in 2001 of the Johns Hopkins Malaria Research Institute (JHMRI).

To help promote cooperation among the various entities now working to combat malaria, JHMRI and the Academy cosponsored a meeting on October 24, 2007 focusing on recent developments in vaccine research.


Sponsorship

This conference and eBriefing were made possible with support from:

Progress in Antimalarial Drug Development


Chris Hentschel (Medicines for Malaria Venture)

The RTS,S Vaccine Shows Promise Against Malaria


Christian Loucq (The PATH Malaria Vaccine Initiative)

Web Sites

Global Alliance for Vaccines and Immunizations (GAVI)
The GAVI Alliance is a unique, multi-dimensional partnership of public and private sector resources with a single, shared focus: to improve child health in the poorest countries by extending the reach and quality of immunization coverage within strengthened health services.

Johns Hopkins Malaria Research Institute
The JHMRI is drawing leading researchers from around the world with the goal of understanding the Plasmodium parasite, the mosquito, and the genes and proteins involved in the transmission of malaria.

Malaria Foundation International
The MFI is a nonprofit organization, dedicated to the fight against malaria since 1992. This website was created in 1995 to provide a central source of information about this devastating disease. The MFI works in partnership with many individuals and groups who have since joined this cause. The MFI's goals are to support awareness, education, training, research, and leadership programs for the immediate and long term development and application of tools to combat malaria.

Medicines for Malaria Venture
A nonprofit organization created to discover, develop and deliver new antimalarial drugs through effective public-private partnerships.

National Institute of Allergy and Infectious Diseases (NIH)
NIAID sponsors research on malaria, provides resources for researchers, lists partners, and releases reports and summaries of their activities.

Nature Magazine — Malaria Focus
Nature published the complete genome sequence of Plasmodium falciparum, the main cause of human malaria and the complete sequence of Plasmodium yoelii, the infectious agent in rodent malaria. The malaria special issue also contains state-of-the-art global genomic analysis of the primary sequence.

PATH Malaria Vaccine Initiative
The PATH Malaria Vaccine Initiative is a focused vaccine development program created in 1999 through a grant from the Bill & Melinda Gates Foundation.

World Health Organization — Malaria
The World Health Organization's Web site on malaria contains basic information about malaria as well as information about worldwide efforts to eradicate the disease and guidelines for treatment (PDF, 1.85 MB).


Publications

Chris Hentschel

Bathurst I, Hentschel C. 2006. Medicines for Malaria Venture: sustaining antimalarial drug development. Trends Parasitol. 22: 301-307.

Hentschel C, Moree M. 2006. Malaria research. Lancet Infect. Dis. 6: 123.

Hentschel CC. 2004. Public-private partnerships: new ways to discover, develop and deliver drugs for tropical diseases. Southeast Asian J. Trop. Med. Public Health 35 Suppl 2: 1-4.

Christian Loucq

Aponte JJ, Aide P, Renom M, et al. 2007. Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial. Lancet 370:1543-1551.

Macete EV, Sacarle J, Aponte JJ, et al. 2007. Evaluation of two formulations of adjuvanted RTS, S malaria vaccine in children aged 3 to 5 years living in a malaria-endemic region of Mozambique: a Phase I/IIb randomized double-blind bridging trial. Trials 8: 11. Full Text

Marcelo Jacobs-Lorena

Abraham EG, Donnelly-Doman M, Fujioka H, et al. 2005. Driving midgut-specific expression and secretion of a foreign protein in transgenic mosquitoes with AgAper1 regulatory elements. Insect Mol. Biol. 14: 271-279.

Abraham EG, Pinto SB, Ghosh A, et al. 2005. An immune-responsive serpin, SRPN6, mediates mosquito defense against malaria parasites. Proc. Natl. Acad. Sci. USA 102: 16327-16332. Full Text

Dinglasan RR, Alaganan A, Ghosh AK, et al. 2007. Plasmodium falciparum ookinetes require mosquito midgut chondroitin sulfate proteoglycans for cell invasion. Proc. Natl. Acad. Sci. USA 104: 15882-15887.

Dinglasan RR, Kalume DE, Kanzok SM, et al. 2007. Characterization of a novel, conserved Plasmodium transmission-blocking mosquito midgut antigen. Proc. Natl. Acad. Sci. USA 104: 13461-13466.

Marrelli MT, Li C, Rasgon J, Jacobs-Lorena M. 2007. Transgenic malaria-resistant mosquitoes have a fitness advantage when feeding on Plasmodium-infected blood. Proc. Natl. Acad. Sci. USA 104: 5580-5583. Full Text

Moreira CK, Rodrigues FG, Ghosh A, et al. 2007. Effect of the antimicrobial peptide gomesin against different life stages of Plasmodium spp. Exp. Parasit. 116: 346-353. Full Text

Riehle MA, Moreira CK, Lampe D, et al. 2007. Using bacteria to express and display anti-Plasmodium molecules in the mosquito midgut. Int. J. Parasit. 37: 595-603.

Susan Kraemer

Kraemer SM, Kyes S, Aggarwal G, et al. 2007. Patterns of gene recombination shape var gene repertoires in Plasmodium falciparum: comparisons of geographically diverse isolates. BMC Genomics 8: 45. Full Text

Kraemer SM, Smith JD. 2006. A family affair: Var genes, PfEMP1 binding, and malaria disease. Curr. Opin. Microbiol. 9: 374-380.

Kraemer SM, Smith JD. 2003. Evidence for the importance of genetic structuring to the structural and functional specialization of the Plasmodium falciparum var gene family. Mol. Microbiol. 50: 1527-1538.

Kyes SA, Kraemer SM, Smith JD 2007. Antigenic variation in Plasmodium falciparum: gene organization and regulation of the var multigene family. Eukaryot. Cell 6: 1511-1520. Full Text

Trimnell A, Kraemer SM, Mukherjee S, et al. 2006. Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria. Mol. Biochem. Parasitol. 148: 169-180.

Nirbhay Kumar

Leblanc R, Vasquez Y, Hannaman D, Kumar N. 2007. Markedly enhanced immunogenicity of a Pfs25 DNA-based malaria transmission-blocking vaccine by in vivo electroporation. Nov 20; [Epub ahead of print]

Liu Y, Promeneur D, Rojek A, et al. 2007. Aquaporin 9 is the major pathway for glycerol uptake by mouse erythrocytes, with implications for malarial virulence. Proc. Natl. Acad. Sci. USA 104: 12560-12564.

Mlambo G, Vasquez Y, LeBlanc E, et al. [in press]. An RT-PCR based detection of Plasmodium falciparum gametocytes using blood collected on filter papers. Am. J. Trop. Med. Hyg.

Okulate M, Kalume DE, Kristiansen T, et al. 2007. Identification and molecular characterization of a novel protein SAGLIN recognized by monoclonal antibodies affecting infectivity of Plasmodium sporozoite infectivity of salivary glands in An. gambiae. Insect Mol. Biol. 16: 711-722.

Sungano Mharakurwa

Mharakurwa S. 2004. Plasmodium falciparum transmission rate and selection for drug resistance: a vexed association or a key to successful control? Int. J. Parasitol. 34: 1483-1487.

Mharakurwa S, Mutambu SL, Mudyiradima R, et al. 2004. Association of house spraying with suppressed levels of drug resistance in Zimbabwe. Malar. J. 3: 35. Full Text

Mharakurwa S, Simoloka C, Thuma PE, et al. 2006. PCR detection of Plasmodium falciparum in human urine and saliva samples. Malar. J. 5: 103. Full Text

Douglas Norris

Kent RJ, Thuma P, Mharakurwa S, Norris DE. 2007. Seasonality, blood feeding behavior and transmission of Plasmodium falciparum by Anopheles arabiensis following an extended drought in Southern Zambia. Am. J. Trop. Med. Hyg. 76: 267-274.

Kent RJ, Mharakurwa S, Hamapumbu H, Norris DE. 2007. Recognition of a novel melanotic mutant in a field population of Culex pipiens quinquefasciatus Say in Southern Zambia. J. Am. Mosq. Control Assoc. 23: 71-75.

Kent RJ, Mharakurwa S, Norris DE. 2007. Spatial and temporal genetic structure of Anopheles arabiensis in Southern Zambia over consecutive wet and drought years. Am. J. Trop. Med. Hyg. 77: 316-323.

David J. Sullivan

Chen X, Chong CR, Shi L. 2006. Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity. Proc. Natl. Acad. Sci. USA 103: 14548-14553. Full Text

Jain SK, Persaud D, Perl TM, et al. 2005. Nosocomial malaria and saline flush. Emerg. Infect. Dis. 11: 1097-1099. Full Text

Nyunt M, Pisciotta J, Feldman AB, et al. 2005. Detection of Plasmodium falciparum in pregnancy by laser desorption mass spectrometry. Am. J. Trop. Med. Hyg. 73: 485-490.

Keynote Speaker

Chris Hentschel, PhD

Medicines for Malaria Venture
e-mail | web site | publications

Chris Hentschel is president and chief executive officer of the Medicines for Malaria Venture (MMV) in Geneva, Switzerland. MMV is a not-for-profit foundation that aims to facilitate the discovery, development and delivery of affordable new drugs for the treatment of malaria. He graduated in biochemistry from King's College, London, UK, and obtained a doctorate from the same institution. His early career focused on basic biomedical research, at the Imperial Cancer Research Fund, London, as a lecturer at the Swiss Federal Institute of Technology (ETH), Zurich, and finally as a Fogarty Fellow at the National Institutes of Health, Bethesda, MD, USA.

From 1978–1997, Hentschel served as chief executive oficer and scientific director of the UK Medical Research Council's Collaborative Centre. He was head of the Department of Molecular Genetics at Celltech from 1983–1987. In 1999 he became a senior research fellow of the Emerging Technology Program of the Wharton Business School. Hentschel is also a non-executive director to two biotechnology companies, an advisor to a European venture capital fund, and member of the Supervisory Board of the Global Medical Forum, Zurich and of the High-level Advisory Panel for Global Health Innovations project at the Saïd Business School, Oxford. Hentschel is currently an interim member of the Executive Committee of the Roll Back Malaria (RMB) Partnership.

Speakers

Peter Agre, MD

Johns Hopkins Malaria Research Institute
web site | publications

Peter Agre was introduced as the new director of the Johns Hopkins Malaria Research Institute at the October 24, 2007, meeting Progress against Malaria: Developments on the Horizon, held at the New York Academy of Sciences. Agre attended medical school at Johns Hopkins and received his MD in 1974. Following an Internal Medicine Residency at Case Western Reserve University Hospitals of Cleveland and a Hematology–Oncology Fellowship at the University of North Carolina at Chapel Hill, Agre returned to Johns Hopkins as a postdoctoral fellow in the Department of Cell Biology in the laboratory of Vann Bennett.

Agre joined the faculty at Johns Hopkins School of Medicine in 1984 and rose through the ranks to professor of biological chemistry and professor of medicine. Agre also took a sabbatical in the laboratory of Steven McKnight at the Carnegie Institution of Washington. After nearly three decades at Johns Hopkins, Agre moved to Duke University School of Medicine in 2005 where he was vice chancellor for science and technology and professor of cell biology and professor of medicine.

Agre's research led to the first discovery of membrane defects in congenital hemolytic anemias (spherocytosis) and produced the first isolation of the Rh blood group antigens. In 1992, Agre's lab became widely recognized for discovering the aquaporins, a family of water channel proteins found throughout nature and responsible for numerous physiological processes in humans— including kidney concentration, as well as secretion of spinal fluid, aqueous humor, tears, sweat, and release of glycerol from fat. Aquaporins have been implicated in multiple clinical disorders—including fluid retention, bedwetting, brain edema, cataracts, heat prostration, and obesity. Water transport in lower organisms, microbes, and plants also depend upon aquaporins. For this work, Agre shared the 2003 Nobel Prize in Chemistry with Roderick MacKinnon of Rockefeller University.

Agre was elected to the National Academy of Sciences in 2000, where he serves as chairman of the Committee for Human Rights, and he was elected to the Institute of Medicine in 2005. He was also elected to the American Academy of Arts and Sciences in 2003, and the American Philosophical Society in 2004. He also holds numerous other honors and awards.

Diane Griffin, PhD, MD

Johns Hopkins Bloomberg School of Public Health
e-mail | web site | publications

Diane Griffin received her PhD and MD in 1968 from Stanford University. Griffin has studied host immune responses to viral infections since she first arrived at Johns Hopkins in 1970. She is currently the Alfred and Jill Sommer Professor and Chair of the Johns Hopkins Bloomberg School of Public Health's W. Harry Feinstone Department of Molecular Microbiology and Immunology.

Griffin's research focuses on how viruses cause disease. For example, Sindbis virus is transmitted by mosquitoes and causes encephalitis, an inflammation of the brain, in mammals and birds. She has studied how the virus infects and then kills selected nerve cells in mice and has identified ways that the immune system can clear the virus from neurons without harming the nerve cells themselves.

Griffin is a member of the Institute of Medicine and the National Academy of Sciences. She is a fellow of the American Association for the Advancement of Science, the American Academy of Microbiology and the Infectious Disease Society of America. Griffin is the past-president of the American Society for Microbiology.

Marcelo Jacobs-Lorena, PhD

Johns Hopkins Malaria Research Institute
e-mail | web site | publications

Marcelo Jacobs-Lorena received a bachelors of science in chemistry from the University of São Paulo, Brazil, in 1964. He then went to Japan (Osaka University, Osaka) where he worked on the elucidation of the genetic code by sequencing wild type and double-frame-shift mutants of T4 phage lysozyme, receiving a master's degree in 1967. Jacobs-Lorena received his PhD from the Massachusetts Institute of Technology in 1972, working on mechanisms of protein synthesis and on the characterization of maternal mRNAs from sea urchins.

He did postdoctoral training from 1972 to 1977 at the University of Geneva (Switzerland) working on gene expression during Drosophila oogenesis. In 1977 he joined the faculty of Case Western Reserve University, where he initially worked on the developmental genetics of early Drosophila development and then, under the initial sponsorship of the MacArthur Foundation, on insect vectors of disease. Since 2003 he has been a professor at the Johns Hopkins School of Public Health. Current research in his laboratory centers on the elucidation of molecular interactions between the mosquito and the malaria parasite and on ways to interfere with development of the malaria parasite in the mosquito.

Michael J. Klag, MD, MPH

Johns Hopkins Bloomberg School of Public Health
e-mail | web site | publications

Michael J. Klag is dean of the Johns Hopkins Bloomberg School of Public Health. He received his MD from the University of Pennsylvania in 1978.

After completing residency and chief residency in internal medicine at the State University of New York Upstate Medical Center, he served in the U.S. Public Health Service. In 1984, he moved to Johns Hopkins as a general internal medicine fellow and obtained a master of public health degree from the Johns Hopkins School of Hygiene and Public Health in 1987. That year, Klag joined the faculty in the Department of Medicine. In 2005, Klag was the inaugural holder of the David M. Levine Professorship of Medicine.

Since 1987, he also has held joint appointments in the departments of Epidemiology and Health Policy and Management. Early in his career, he was director of the clinical track of the school's residency program in preventive medicine.

Klag's research has centered on the prevention, epidemiology, and treatment of hypertension and kidney disease. He directs the Johns Hopkins Precursors Study, a prospective study of Hopkins medical students that began in 1946 and continues to follow participants. This study has made seminal contributions to our understanding of how characteristics in young adulthood influence health and disease later in life.

Klag also has led pioneering studies in kidney disease epidemiology, including the first study to assess the incidence of end-stage renal disease and to identify blood pressure as a risk factor for the development of kidney failure. His work has laid the foundation for numerous subsequent studies.

Throughout his career, Klag has served in a number of leadership roles, including director of the Division of General Internal Medicine, interim director of the Department of Medicine, and, currently, vice dean for clinical investigation. He was editor in chief of the Johns Hopkins Family Health Book.

Susan Kraemer, PhD

Johns Hopkins Malaria Research Institute
e-mail | web site | publications

Susan Kraemer joined the Department of Molecular Microbiology and Immunology and the Johns Hopkins Malaria Research Institute as an assistant professor in the summer of 2007. She obtained an MS in Health Physics from Colorado State University in 1995, and a PhD in Radiation Biology and Molecular Cellular Biology from Colorado State University in 1996.

After receiving her PhD, she worked in yeast genetics studying the regulation of transcription. During that time, she decided to change fields and study malaria. She then spent five years at Seattle Biomedical Research Institute in Seattle, WA, before moving to Johns Hopkins University.

The intent of her research is to understand the genetic and biological mechanisms involved in the pathogenesis and evolution of the human malaria parasite Plasmodium falciparum in order to aid vaccine development and the identification of new effective drugs.

Her lab will focus on two research directions. The first involves understanding the mechanisms of antigenic variation, a process that allows malaria parasites to rapidly change the molecules on the red cell surface to avoid the host's immune response. These molecules are encoded in the parasite's genome by multicopy, nonallelic gene families. Since some members of these gene families are current vaccine candidates, we are undergoing studies to understand the levels of diversity and conservation of these gene families and the extent that they are expressed during disease.

The second involves studying genetic recombination and DNA repair in malaria parasites. It has been shown that homologous recombination and DNA repair pathways may be involved in the evolution of variant gene families and in the generation of mutations that can cause drug resistance. To better understand how diversity is obtained in the parasite's variant antigen repertoires and how drug resistance develops, her lab is developing methods to dissect the mechanisms of DNA repair and recombination in Plasmodium falciparum.

Nirbhay Kumar, PhD

Johns Hopkins Malaria Research Institute
e-mail | web site | publications

Nirbhay Kumar obtained a MSc in 1972 in Biochemistry from Banaras Hindu University, Varanasi, India, and his PhD in 1977 in Biochemistry from All India Institute of Medical Sciences, New Delhi.

Kumar's studies focus on the biochemistry, molecular biology, and immunology of antigens expressed in the sexual stages of malaria parasite and host-parasite interaction. Some of the major projects include: (i) molecular mechanisms of sexual differentiation in Plasmodium, (ii) the development of a malaria transmission blocking vaccine, (iii) differential gene expression during male gametogenesis, (iv) signal-transduction mechanisms in sexual differentiation (v) molecular mechanisms involved in sexual compatibility among different P. falciparum isolates, (vi) molecular characterization of malarial 'recombinosome', (vii) immuno and molecular epidemiology of malaria studies in Zimbabwe and Zambia, (viii) immunobiological significance, and role of malarial heat shock proteins in host-parasite adaptation, (ix) co-infections involving malaria using mouse models and in humans and (x) malaria detection methods.

Christian Loucq, MD

The PATH Malaria Vaccine Initiative
e-mail | web site

Christian Loucq directs the PATH Malaria Vaccine Initiative (MVI), which seeks to accelerate the development of promising malaria vaccines and ensure their availability and use in developing countries. Loucq has more than 30 years of experience in medicine, pharmaceuticals, vaccines, and global health. He joined MVI in February 2007, serving as director of Strategy and Operations and as interim director until his appointment as MVI director three months later.

His professional experience spans the globe: Born and educated in France, he has lived and worked in Algeria, Belgium, Chad, China, India, the Netherlands, Niger, Switzerland, Thailand, and the United Kingdom. Loucq has managed vaccine businesses in China, India, and Thailand and has been involved in most stages of vaccine development. He has worked with large vaccine companies, such as GlaxoSmithKline and Sanofi Pasteur, and biotech companies including Rhein Biotech and Acambis. He has extensive experience partnering with local governments, building public-private partnerships, and setting up local private collaborations.

Loucq earned his state doctorate of human medicine at the University of Paris X and a diploma of public health and tropical medicine from the University of Aix-Marseilles.

Sungano Mharakurwa, PhD

Johns Hopkins Malaria Research Institute
e-mail | web site | publications

Sungano Mharakurwa joined the JHMRI in 2003 as a research associate in Molecular Microbiology and Immunology and project manager for the Malaria Institute at Macha. His primary research interest is in the molecular epidemiology of drug resistance in Plasmodium falciparum. He is concluding a study of the association between malaria transmission and the evolution of drug resistance, and preliminary results suggest that reduced transmission from house spraying with residual insecticides may suppress the development of chloroquine resistance.

Mharakurwa received his BSc in 1990 from the University of Zimbabwe, an MSc in 1993 from the London School of Hygiene & Tropical Medicine, UK and a PhD in 2001 from Oxford University, UK.

Douglas Norris, PhD

Johns Hopkins Malaria Research Institute
e-mail | web site | publications

Douglas Norris is an assistant professor in the Department of Molecular Microbiology and Immunology and a member of the Johns Hopkins Malaria Research Institute.

Research in Norris' laboratory is focused on the biology and ecology of several arthropod-borne disease systems, with special emphasis on the genetic diversity within, and the genetic structuring of, arthropod and arthropod-borne pathogen populations.

Norris is currently carrying out research in southern Zambia where his team investigates the biology, behavior, and genetics of mosquitoes involved in malaria transmission. His team has developed several molecular tools for unraveling feeding behavior as it relates to transmission intensity and therefore burden of human disease. Norris has been studying the genetics of mosquitoes that transmit malaria since 1997, and has expanded that research to include gene flow and the movement of insecticide resistance in southern African mosquito populations. Little is known about the levels of insecticide resistance in Zambia, despite resistance having a potentially enormous impact on the control of mosquito-borne diseases. Norris has also been involved and maintains interests in West Nile virus and tick-borne diseases, especially Lyme disease and rickettsial pathogens.

In addition to his research, Norris is involved in graduate training at Johns Hopkins Bloomberg School of Public Health and abroad. He has extensive international research and field experience in Africa and Asia. Norris is a former president of the Acarology Society of America and is a councilor and officer for the American Committee on Medical Entomology. He is also currently serving on several advisory, executive, and editorial boards for professional societies and journals, and is an author of over 50 scientific papers. Norris has an MS degree in Entomology from North Carolina State University, a PhD in Microbiology from Colorado State University, and he completed his postdoctoral training focused on the population genetics of malaria mosquitoes in West Africa at the University of Texas Medical Branch.

David Sullivan, MD

Johns Hopkins Malaria Research Institute
e-mail | web site | publications

David Sullivan received his MD in 1988 from the University of Alabama at Birmingham. His current research investigates new diagnostic tools, mechanism of drug action, and epidemiology of drug resistance for P. falciparum.

The laboratory is developing ELISA based HRP II and aldolase antigen testing to make quantitative determination of parasitemia in serum and urine. A hemozoin detection test by the method of mass spectroscopy is in development with Peter Scholl, Nirbhay Kumar, and reseachers at the JHU Applied Physics Lab.

The lab also focuses on metal metabolism perturbed by antimalarial chemotherapy. They investigate the formation of iron rich hemozoin heme crystals and its inhibition by the quinolines. The lab is also investigating the basic cell biology of iron, copper, and zinc by characterization of genes for metal storage, transport, and respective chaperones. They are developing mass spectroscopy for defining the metabolome (metabolites not encoded by the genome) to compare with the transcriptome in the investigation of drug effects on the parasite. The laboratory is also screening a library of over 2000 available FDA-approved drugs for malaria inhibition.

The laboratory is performing PCR-based genotyping of drug resistance genes for chloroquine, antifolates, and mefloquine from fingerprick samples of blood on filter paper. In addition they are utilizing microsatellite allele determination in collaboration with Douglas Norris for assessment of multiplicity of infection and duration of infection in longitudinal studies.

The lab is also studying the interaction of HIV and malaria during pregnancy.


Marilynn Larkin

web site

Marilynn Larkin is a medical editor, journalist, and videographer based in New York City. Her work has frequently appeared in, among others, The Lancet, The Lancet Infectious Diseases, and Reuters Health's professional newswire. She has served as editor of many clinical publications and is author of five medical books for general readers as well as Reporting on Health Risk, a handbook for journalists. She is currently head of publications for The Society for Biomolecular Screening.

In 2004, Ms. Larkin started her own fitness consulting company (www.mlarkinfitness.com), and developed a class, Posture-cize, that helps people improve their posture, increase productivity, and reduce injury.

Taking on a deadly opponent

Malaria is the leading cause of mortality and morbidity in the world, causing 300 to 500 million infections annually and between 1 and 3 million deaths, mostly among children. Every 30 seconds a child dies of malaria—that's 2000 lives lost per day.

Ninety percent of malaria's victims live in Africa, where the disease spawned by P. falciparum accounts for about one in five of all childhood deaths (Rugemalila et al, 2006). The fact that malaria continues to exact a terrible toll in less developed nations despite near eradication in developed countries provided the impetus for the creation in 2001 of the Johns Hopkins Malaria Research Institute (JHMRI).

To help promote cooperation among the various entities now working to combat malaria, JHMRI and the Academy cosponsored a meeting on October 24, 2007 focusing on recent developments in vaccine research. The Institute also took this opportunity to announce the appointment of Nobel laureate Peter Agre as its new director.

A global, local disease

In his keynote address, Chris Hentschel, president and chief executive officer of Medicines for Malaria Venture (MMV), made the point that while malaria is most devastating in Africa, it also takes a large toll in India, although the disease there is mainly due to the less virulent P. vivax. About 3 to 4 million cases are "officially" reported, but the amount of antimalarials provided to the country suggests the toll may be as much as 10 times that amount, he said.

The virulence and prevalence of malaria differs not only from country to country, but from community to community, Hentschel observed. "This is important because what we can hope to achieve in the future depends on the understanding that malaria is a global, local disease. What is sensible to do [to curtail malaria] in one area may be quite different from what is sensible to do in another."

In 1934, efforts to control malaria hit a high point; it seemed that the disease might actually be eradicated with DDT and chloroquine treatment. The so-called "eradication era" (1950–70) "was a failure only for Africa, not rest of the world," Hentschel said. "And when resistant strains emerged, more people started dying from malaria than ever before."

Scientists became demoralized by the failure to eradicate malaria globally. "We didn't eradicate malaria, but we did eradicate malariologists," Hentschel quipped. By 2000 the picture began to change, however. Pairing malaria with AIDS as the two major diseases to attack in Africa, and elsewhere in the less developed world, made it easier to secure funding. This was fortunate because new drugs were needed, but the pipeline for new antimalarials was virtually empty. And so at that point, "we thought it was worth having another go."

The changing climate led to the formation of MMV, an international non-profit organization with the mission to "discover, develop, and deliver new antimalarial drugs through effective public-private partnerships."

MMV moved quickly to establish "product development public-private partnerships" (PDPs), Hentschel explained. The organization works with industry, academia, the public sector, and stakeholders in endemic countries, selecting promising projects and allocating funds for product development. The selected antimalarials must be targeted to people in need and made accessible to them.

Today, the organization is working with over 80 partners and more than 600 scientists and clinicians in 34 countries. It supports more than 30 projects, comprising an antimalarial drug portfolio that includes 19 new classes of drugs.

MMV recently partnered with the Innovative Vector Control Consortium (IVCC)—a group of research institutions supported by a grant from the Bill and Melinda Gates Foundation—to try to bring innovation back into insecticide development, as well. Although new insecticides have been developed for agricultural purposes, "we've had no innovation to support public health for decades," Hentschel commented.

"We have to hit this disease at every point," he emphasized. "Hit the parasite before it gets into the liver, create vaccines, develop new drugs, use indoor residual spraying, put up new bed nets, engineer mosquitoes—whatever it takes," Hentschel concluded.

The quest for a vaccine

In contrast to the overarching goal of MMV, the PATH Malaria Vaccine Initiative (MVI) is a focused vaccine development program created in 1999 through a grant from the Bill and Melinda Gates Foundation. Like MMV, this international non-profit organization collaborates with diverse public- and private-sector partners, including the Global Alliance for Vaccines and Immunizations (GAVI), but with the goal of accelerating the development of promising malaria vaccines and ensuring their availability and accessibility in less developed countries, explained MVI director Christian Loucq.

"We are 'malaria venture idealists'—that's a bit like venture capitalists. We locate and invest in promising candidates to help bring them through preclinical development. And we analyze our return on investment in terms of lives to be saved in Africa," Loucq said.

MVI currently has eight vaccine candidates in various stages of testing, but none more exciting at the moment than RTS,S. As reported in the October 17, 2007, issue of The Lancet, the Malaria-038 trial (MAL 038), conducted in Mozambique, showed that RTS,S has a promising safety and tolerability profile in infants, and provides substantial protection against infection and clinical disease. Several Phase 2 trials are ongoing, but the recent findings provide the impetus for a Phase 3 trial, which is scheduled to start in the second half of 2008.

MVI also provided funding that helped inaugurate an unusual project under the umbrella of Sanaria, a Maryland-based biotech company. Sanaria is developing, and aims to commercialize, a metabolically active, non-replicating (i.e., attenuated) malaria sporozoite vaccine against P. falciparum. Its manufacturing facility allows workers to rear live, aseptically produced mosquitoes; feed them blood containing the malaria parasite; irradiate the insects to weaken the parasites; and then harvest the parasites from the mosquito salivary glands. These parasites are the main component of a vaccine that is scheduled to enter Phase 1 trials later in 2008.

Other vaccine projects are based on various strategies, including the delivery of optimized genes for P. falciparum antigens in adenovirus vectors; the use of P. falciparum blood-stage antigens; and the use of merozoite-stage antigens in recombinant vaccines.

But MVI faces significant challenges, Loucq acknowledged. These include how to make all the researchers work together ("It's nearly impossible," he said), how to find new antigens, how to create new platforms for development, and how to improve efficacy. "We struggle to identify and define the projects or combinations to bring forward, but it all costs money, and creates expectations, and the reality is, we have to also accept failure," Loucq concluded.

Innovative solutions

Because the female Anopheles mosquito spreads Plasmodium from one victim to the next, one goal of research at the Johns Hopkins Malaria Research Institute is to disable this vector. At the Academy, the Institute released a report titled Breaking the Cycle, which outlines the various strategies it is pursuing. Every aspect of malaria, from the biology of the mosquito host-Plasmodium parasite interaction to culturally sensitive diagnostics for the disease, is under investigation at the JHMRI, and several of its researchers were present to explain their novel projects.

Modifying the mosquito

"Unlike HIV and TB, which are delivered directly from person to person, malaria must have an intermediate vector in order for transmission to occur. If we can interfere with parasite development in the mosquito, we will interfere with transmission," said JHMRI's Marcelo Jacobs-Lorena. His group has been exploring different ways to render mosquitoes resistant to malaria parasites.

Earlier studies demonstrated that when transgenic mosquitoes express a gene that interferes with parasite invasion of the midgut, their ability to transmit disease is significantly hampered. The gene encodes a peptide called SM1, which binds to receptors on the surface of midgut and salivary gland epithelia. More recent experiments showed that mosquitoes that secrete SM1 into the hemocoel (instead of the midgut) are also hampered in their ability to transmit parasites, presumably because sporozoites can no longer invade the salivary gland.

Importantly, these genetically modified mosquitoes are as fit as their wild-type counterparts. And, when they fed on mice infected with P. berghei, the transgenic mosquitoes actually survived longer than their non-transgenic counterparts, presumably because infection by the parasite also weakens non-transgenic mosquitoes. This means, in theory at least, that transgenic mosquitoes could eventually endure long enough to replace disease-carrying mosquitoes in nature. But finding a way to introduce SM1 into mosquito populations seems to be an insurmountable challenge, Jacobs-Lorena concedes.

The group also tried another strategy to thwart transmission: introducing the SM1 gene into the bacteria of the midgut instead of into the mosquito itself, a process called paratransgenesis. But although they could make transgenic bacteria that produced the same effector gene, the problem of introducing the bacteria into the field remained.

On another front, the group is working to identify potential mosquito midgut epithelial receptors that the parasite needs to recognize in order to invade this cell layer. One is aminopeptidase N1 (APN1). Antibodies against APN1 have been shown to recognize midgut aminopeptidases from diverse anopheline species, thereby interfering with the parasite life cycle, Jacobs-Lorena said. APN1 is now considered a candidate "universal" transmission-blocking antigen.

Vaccinating a village

JHMRI's Nirbhay Kumar and colleagues are taking a different approach to blocking parasite transmission: a transmission-blocking DNA vaccine that interferes with the parasite's sexual development. "The idea would be to immunize people in a community, so the antibodies would be picked up during a blood feed and block parasite development in the mosquito. No parasite, no transmission," explained Kumar.

One candidate vaccine, Pf s 25, when evaluated in mice as a DNA vaccine, effectively blocked transmission of malaria parasites to mosquitoes by more than 90%. But the DNA vaccine was not as effective in monkeys; although it was immunogenic, the monkeys needed a prime boost with a recombinant protein before it showed efficacy. The team is now using various lipid formulations and other methods of vaccine delivery, one in particular known as in vivo electroporation, in an effort to improve efficacy while lowering the required "dose" of DNA. Soon-to-launch trials in baboons in Kenya will help determine whether the vaccines can be used in humans some day, Kumar concluded.

Using a living laboratory

JHMRI's Douglas Norris is one of the primary scientists at a research field and training station in Macha, in rural Zambia. "We're sitting next to a hospital, so we're in a good position to bridge the gap from lab to field," Norris explained. Macha has brought together scientists and clinicians with expertise in clinical disease, epidemiology, parasitology, immunology, ecology, genetics, and related areas so that the surrounding community can serve as a "living laboratory" for different kinds of research. The team educates local staff and community members about the importance of their involvement in studies that include rapid diagnostics, disease severity, mosquito biology and distribution, and environmental surveillance.

Improving diagnostic strategies

A definite diagnosis of malaria can only be made by venipuncture or drawing blood. This leads to tremendous limitations in the field, because these techniques require trained personnel, raise biosafety concerns (safe use and disposal of sharps) and problems with compliance, explained JHMRI's Sungano Mharakurwa. "We're often called Satanists because we take blood," he said.

For all these reasons, Mharakurwa and his colleagues are testing whether saliva can be used as a diagnostic tool. But before this can be done effectively, the team needs to determine first whether the infection in saliva is the same as in the blood sample (recent studies suggest that it is), and then maximize detection, sensitivity, and specificity. So far, the team has shown a proof of concept that P. falciparum can be detected effectively by PCR both in saliva and urine. If the saliva test withstands further testing, it would be a noninvasive tool that is readily available, engenders better community cooperation, and offers the possibility of "an unlimited number of observations and repeated testing," Mharakurwa concluded.

Along similar lines, JHMRI's David Sullivan is exploring the utility of a urine dipstick for malaria diagnosis. Like saliva, the technique is noninvasive and practical. A prototype of the diagnostic tool showed 88% sensitivity to the parasite in individuals who were already ill. Importantly, in people who were parasitemic but not ill, the test was positive in only 2 of 22 cases. "Now we're comparing urine results with blood testing and trying to improve specificity—to assess where the line is between presentation and before the person becomes sick," Sullivan said.

Tackling parasite tactics

On another research front, JHMRI's Susan Kraemer is investigating mechanisms of antigenic variation, the process that allows malaria parasites to rapidly change the molecules on the red cell surface to avoid the host's immune response. These molecules are encoded in the parasite's genome by gene families, some members of which—such as var2CSA—are current vaccine candidates. Therefore, her group is working to understand the various levels of diversity and conservation of these gene families and the extent to which they are expressed in infected erythrocytes.

In conclusion, as Hentschel observed, "all of these strategies have a single aim: to eradicate malaria." Epidemiological data have shown that for malaria to continue in Africa, "each infected person has to infect at least one other; if it's less than one other, then after a while, the disease will go extinct. Right now, in central Africa, a single infection can generate hundreds more, which is why it's going to be incredibly difficult to eradicate this disease. Having said that, the bottom line is that we're in a much better position now than we have been in a very long time—with new leadership and new pipelines, we have reason to be optimistic."


Marilynn Larkin is a medical editor, journalist, and videographer based in New York City.