Progress against Malaria: Developments on the Horizon

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

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.

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.