New England Journal of Medicine
Volume 361 — July 30, 2009 — Number 5
Malaria Control — Addressing Challenges to Ambitious Goals
C. C. Campbell
Over the past 5 years, we have witnessed remarkable progress in malaria control. In Africa, the approach has been to “scale up for impact”1 by rapidly deploying insecticide-treated nets and providing artemisinin-based combination therapy. Programs in Equatorial Guinea, Ethiopia, Rwanda, Zambia, and Zanzibar have shown that when coverage of these interventions exceeds 50 to 60% of the population, the prevalence of infection with malaria parasites and mortality among children from such infection falls by 20 to 25% within 12 to 36 months.2
Progress has been based on highly effective and affordable malaria-control tools and mobilization of substantial funding at the global and national levels. Through the Global Fund to Fight AIDS, Tuberculosis and Malaria, almost $7 billion has been allocated for malaria programs since 2000.
Demonstration of the health effects that can be achieved with current control tools has sparked ambitions. Eradication of malaria is now the global goal. This has prompted comprehensive strategic planning, including the Global Malaria Action Plan3 and the Malaria Eradication Research Agenda,4 to prioritize investments in research and development.
History teaches that malaria-control interventions have inherent life expectancies. Resistance, notably that of Plasmodium falciparum, evolves as the intensity of drug use increases. The studies reported on in this issue of the Journal by Dondorp et al.5 (ClinicalTrials.gov number, NCT00493363 [ClinicalTrials.gov] , and Current Controlled Trials number, ISRCTN64835265 [controlled-trials.com] ) and Noedl et al.6 add to our understanding of the clinical and laboratory characterization and geographic distribution of artemisinin-resistant P. falciparum in Southeast Asia.
The artemisinin compounds are unique in the rapidity with which they kill malaria parasites. To minimize the development of resistance, artemisinins are combined with a second drug with a distinct mode of killing the malaria parasite. This artemisinin-based combination therapy has become the standard of treatment for malaria.
Resistance to malaria drugs has consistently emerged in Asia, specifically in western Cambodia, and spread to all areas with P. falciparum, except Central America and Hispaniola. Recent reports have sounded the alarm regarding a problem with the sensitivity of malaria parasites to artemisinin-based combination therapy. Dondorp et al. document a significant delay in parasitologic clearance in patients in western Cambodia.
They found that the delayed clearance derives from an impaired response to the artesunate component, not to the partner compound, mefloquine.
Using in vitro methods to characterize falciparum parasites from Bangladesh to the Thailand–Cambodia border, Noedl et al. demonstrate a significantly increased 50% inhibitory concentration of dihydroartemisinin required for parasites at sites on the Thailand–Cambodia border.
There is no question that this is resistance to artemisinin; history warns that it will intensify and spread unless containment steps are taken. Has the approach of combination therapy failed to protect the efficacy of artemisinin? Not necessarily. The most likely culprit is the widespread use of artemisinin as monotherapy in this region. To contain artemisinin resistance will require an understanding of human movement, limitation of the use of unregulated drug formulations and doses, and a rethinking of ineffective malaria-transmission control policies.
An intensive campaign coordinated by the World Health Organization has been launched to contain artemisinin resistance. The containment plan involves the rapid deployment of an efficacious artemisinin drug paired with an intensive effort to detect and rapidly treat all malaria infections. Deployment of insecticide-treated nets to decrease malaria transmission and screening and the treatment of migrants will be intensified, and more-thorough mapping of the geographic boundaries of the resistant parasites will be ramped up.
Modeling conducted by Maude et al.7 suggests that malaria transmission must be eliminated to snuff out the last resistant parasites. Is such elimination possible, or is the geographic expansion of artemisinin resistance inevitable? Slowing the spread of resistance will buy valuable time and save lives in the process. There is no alternative class of malaria drugs ready to replace the artemisinin derivatives.
The article in this issue by Roestenberg et al.8 (ClinicalTrials.gov number, NCT00442377 [ClinicalTrials.gov] ) adds evidence that the multidecade effort to develop malaria vaccines is on a positive trajectory. Their report reminds us that the whole malaria parasite is the most potent immunizing antigen identified to date.
Roestenberg et al. report on the immunization of human volunteers by means of repeated exposure to live P. falciparum sporozoites through bites of sporozoite-infected Anopheles stephensi mosquitoes. On subsequent challenge with mosquitoes infected with the same parasite strain, parasitemia developed in none of the 10 immunized volunteers but did develop in all 5 nonimmunized volunteers. Although the mosquito-inoculation approach used cannot be the basis for a human malaria vaccine, there has been considerable progress in the development of attenuated sporozoites that are sterile and standardized; products of these efforts are now entering clinical trials.9
Collins and Jeffery10 demonstrated that the inoculation of humans by P. falciparum sporozoites induces protection against the subsequent challenge of sporozoites with the same parasite strain. Over a 30-year period, radiation-attenuated sporozoites have been shown to be a potent immunogen, protecting more than 90% of subjects against infection.11
Currently, two approaches to the development of a malaria vaccine — the uses of whole parasites and subunit constructs — show promise. A recent study in the Journal by Abdulla et al.12 tested the RTS,S/AS02D candidate vaccine, which contains a subunit antigen targeting the hepatocyte stage of parasite development. The authors demonstrated an efficacy against first infection with P. falciparum malaria of approximately 65%. RTS,S is currently in phase 3 trials in several sites in Africa.
Malaria vaccines are moving from the laboratory into the real world. The vaccines that make it through testing and licensing will be deployed as part of malaria-control programs that distribute insecticide-treated bed nets and as an adjunct to control measures. Vaccines that can prevent, not just delay, the onset of infection would be a major plus in the endgame with falciparum transmission.
We are learning which approaches and time frames will be required to finish off malaria in the most challenging regions. The certainty is that new drugs active against artemisinin-resistant P. falciparum will be needed, possibly soon. Investment in a multipronged approach to vaccine development is imperative. Technical impediments to progress can be resolved.
The coming 5 years will be decisive. Will there be a sustained commitment to deploying lifesaving interventions to reach a majority of persons at risk for malaria? Will national leaders and global financing agencies balance near-term success with longer-term programs and ensure that investment in research and development of new technologies remains a priority? The answer must be yes. The question is how. Millions of African children await the answer.
No potential conflict of interest relevant to this article was reported.
From the Malaria Control Program, Program for Appropriate Technology in Health (PATH), Seattle.
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Global Malaria Action Plan for a malaria-free world. Geneva: Roll Back Malaria Partnership, 2009. (Accessed July 10, 2009, at http://rbm.who.int/gmap/index.html.)
Malaria Eradication Research Agenda (malERA) home page. (Accessed July 10, 2009, at http://malera.tropika.net/.)
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Noedl H, Socheat D, Satimai W. Artemisinin-resistant malaria in Asia. N Engl J Med 2009;361:540-541. [Free Full Text]
Maude RJ, Pontavornpinyo W, Saralamba S, et al. The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia. Malar J 2009;8:31-31. [CrossRef][Medline]
Roestenberg M, McCall M, Hopman J, et al. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med 2009;361:468-477. [Free Full Text]
Luke TC, Hoffman SL. Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuated Plasmodium falciparum sporozoite vaccine. J Exp Biol 2003;206:3803-3808. [Free Full Text]
Collins WE, Jeffery GM. A retrospective examination of secondary sporozoite- and trophozoite-induced infections with Plasmodium falciparum: development of parasitologic and clinical immunity following secondary infection. Am J Trop Med Hyg 1999;61:Suppl:20-35. [Abstract]
Hoffman SL, Goh LM, Luke TC, et al. Protection of humans against malaria by immunization with radiation attenuated Plasmodium falciparum sporozoites. J Infect Dis 2002;185:1155-1164. [CrossRef][Web of Science][Medline]
Abdulla S, Oberholzer R, Juma O, et al. Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med 2008;359:2533-2544. [Free Full Text]