Time to Eradicate Malaria?

Malaria has declined significantly worldwide thanks to combination therapy based on artemisinin and the use of insecticide-impregnated mosquito nets; this has raised hopes for eradicating the disease by developing additional drugs and vaccines and the release of transgenic mosquitoes, but is it wise? Prof. Joe Cummins

A number of approaches are being deployed to fight the global scourge of malaria. These include the development of genetically modified mosquitoes that do not transmit the malaria parasite to replace the disease causing mosquitoes, vaccines to prevent parasite infection, insecticides and treated sleeping nets to protect against mosquito bites, and drugs to treat those infected by the disease parasite. I-SIS first reviewed these in 2001 [1] (Two takes on Malaria -Transgenic Mosquitoes Coming-Rolling Back Malaria*, SiS 13/14)

The development of malarial vaccines and the risks involved were reviewed in 2009 [2] (Malaria Vaccine Trials Raise Concerns over Risks to Infants, SiS 42)

Emergent decline in malaria incidence

In the past five years, there has been a major decline in the incidence of malaria worldwide, extending from the low incidence to the very high incidence areas of the globe. That amazing decline in malaria was accomplished using the drug artemisinin in combination with another drug to avoid the drug resistance that has hampered treatment in the past; along with the deployment of insecticide treated sleeping nets [3].

However, concerns remain over the reappearance of resistant malaria parasites. The World Health Organization (WHO) has put together a perspective on moving from malaria control to malaria eradication. WHO defines ‘malaria control’ as the reduction of disease burden to a level at which it is no longer a public health problem; ‘malaria elimination’ is interrupting local mosquito-borne transmission in a defined geographical area to 0 incidence of locally contracted cases, while ‘malaria eradication’ is the permanent reduction to 0 of the worldwide incidence of malaria infection [3].

Elimination of malaria requires switching from population-based interventions to effective surveillance and response. Sustained efforts will be required to prevent the resurgence of malaria from where it is eliminated. Eliminating malaria from countries where the intensity of transmission is high and stable such as in tropical Africa will require more potent tools and stronger health systems than are available today. When such countries have effectively reduced the burden of malaria, the achievements will need to be consolidated before contemplating eradication. Malaria control and elimination are under the constant threat from the parasite and vector mosquito developing resistance to medicines and insecticides, which are the cornerstones of current anti-malarial interventions [3].

Artemisinin-based combination therapies

The key to treating malaria is finding drugs that act quickly, resist genetic resistance in the parasite causing malaria, and can be produced economically. Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. The compound is isolated from the plant Artemisia annua. It is produced when the plant is subjected to biotic or abiotic stress.  The drug is derived from a herb used in Chinese traditional medicine for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest record dates back to 200 BC .Use of the drug by itself, in monotherapy, is explicitly discouraged by the WHO as there have been signs that malarial parasites are developing resistance to the drug. Combination therapies that include artemisinin are preferred; and are both effective and well tolerated in patients [4]. Artemisinin treatment was advised by WHO a decade ago, and the monotherapy proved effective; but resistant parasites appeared in southeast Asia, prompting WHO to call for immediate halt of artemisinin monotherapy in 2006. Artemisinin is now combined with another anti-malarial drug to combat the appearance of resistant mutant parasites [5]. China and Vietnam provide 70 percent of the world’s artemisinn while East and South  Africa supply another 20 percent; the remaining 10 percent is produced synthetically [6]. It is reported that the natural and synthetic drugs have equivalent activity while some synthetic artemisins have better, longer lasting properties in the body than the natural product [7].

Some malaria drug makers have ignored the WHO request to stop selling artemisinin monotherapy drugs. Such unscrupulous practices cannot presently be controlled internationally even though they risk the lives of millions who will succumb if artemisinin is lost to resistance [8]. Another problem is the sale of substandard malaria drugs that contain low levels of the active ingredient. For example, an epidemic of malaria appeared in Pakistan in 2003, which was related to the sale of substandard sulfadoxine-pyrimethamine drug containing insufficient active ingredient against the malaria parasite [9]. Exposure to low levels of a malaria drug will enhance selection of resistant mutant strains of the parasite. The international Affordable Medicines Facility-malaria (AMFm) is an innovative financing mechanism designed to expand access to the most effective treatment for malaria, artemisinin-based combination therapies (ACTs), to delay resistance, and to drive artemisinin monotherapy and substandard drugs out of the market;  measures that will save many lives in the long run [10]. 

ACTs are the first line of treatment against malaria. ACTs comprise of semi-synthetic artemisinin derivatives paired with distinct chemical classes of longer acting drugs. The artemisinins are potent against both the pathogenic asexual blood stages and the transmissible sexual stages of the parasite Plasmodium.  The drug combinations increase the rate of clinical and parasitological cures and decrease the selection pressure for the emergence of anti-malarial resistance. However, there has been some concern that ACTs may produce birth defects if women are treated in the first trimester of pregnancy [11].

Eliminating and eradicating malaria with ACTs and insecticides

The WHO World Malaria Report 2008 documented a worldwide decline in malaria as the result of ACTs and insecticides [12]. In Africa, ACTs have been combined with insecticide-treated bed nets and indoor residual pesticide spraying. The typical ACTs include artesunate-amodiaquine or artemether-lumefantrine. Eritrea reported an 80 percent reduction in malaria deaths following the deployment of insect controls and ACTs. Rwanda reported a decline of nearly 60 percent in malaria inpatients during 2006. Zanzibar reported that by 2006, cases and deaths had been reduced by more than 80 percent in comparison with the numbers recorded in 2001 and 2002.  Other areas of Africa also described significant reduction in malaria illness and death associated with the combination of insecticide treatment and ACTs. Reported malaria deaths in six countries in the Americas and the South-East Asia and Western Pacific regions showed a striking decline from 1997 to 2006.  By July 2008, 10 countries worldwide were in the elimination phase of malaria: Algeria, Argentina, Armenia, Egypt, El Salvador, Iraq, Paraguay, Republic of Korea, Saudi Arabia and Turkmenistan. A further 11 countries were in the pre-elimination phase, and seven were attempting to establish malaria-free zones in parts of each country. In January 2007, the United Arab Emirates was the first formerly endemic country since the 1980s to be certified malaria free by WHO.

A remarkable decline in the global deaths and illness from malaria brought about by the combination of ACTs and pesticide-treated bed nets is a necessary first step in malaria eradication but may not be sufficient in achieving the goal of malaria eradication. The malaria parasite may still achieve resistance to the therapy.

The identification of association between malaria treatment failure and specific polymorphisms in the parasite genome or gene copy number has been undertaken. Genetic molecular markers were linked to increased risk of therapy failure [13]. Such studies should improve the early detection and monitoring of drug resistance in the malaria parasite Plasmodium falciparum.

Antimalaria drugs under development

In response to the emergence and spread of resistance to the available antimalarial drugs, there has been a renaissance in the development of new medicines to control the disease. The threat of resistance means that new molecules with novel mechanisms of action are continually required. The drugs being developed include several new versions of ACTs along with drugs targeting previously untouched biochemical pathways and stages in parasite development. The call for the elimination and eradication of malaria has also prompted an extension of the stages of the life cycle of malaria parasites to be targeted by new drugs. In the short term, there should be a group of new ACTs available for use. The challenge will be to better understand how to deploy these for treatment and prophylaxis in those most at risk, young children and pregnant women [14].

The global anti-malaria drug portfolio has changed dramatically in recent years. Within a few years of the WHO announcement that ACTs should be the cornerstone of uncomplicated malaria treatment, new fixed-dose combinations are, or soon will be available. However, because these products are based on the same chemical families, the portfolio needs to be diversified [15]. Almost all the drugs widely used today against Plasmodium target the asexual blood stages of the parasite. It is necessary to develop drugs that will fully inhibit the obligate short-lived hepatic forms that precede blood infections. Such drugs will prevent pathology and interrupt transmission, and could therefore have an important role in the control of malaria and its eventual eradication [16].

An arsenal of ACTs and novel drugs are being developed. For example, A novel method has been developed to rapidly screen millions of chemical compounds for their potential ability to serve as anti-malarial drugs. The chemicals to be tested were maintained as a library of compounds. Compounds to be tested were pre-dispensed in 384-well plates, to which microscopic droplets of growth media were added, and inoculated with the malaria parasite P. falciparum. The plates were incubated for 72 h and then frozen overnight. The growth of the parasite was assessed by the activity of an essential enzyme with a substrate that generates a coloured product, which was scanned on the plates and the data processed by computer. Nearly 2 million chemicals were screened for anti-parasite activity, of which 13 533 compounds were found to inhibit the malaria parasite; and more than 8 000 compounds inhibited the growth of a multi-drug resistant strain of the malaria parasite. Most of the drug candidates are believed to be new. Chemical structures and associated data have been made public to encourage further study and drug development. Of course, there will have to be much more extensive experimentation to identify those chemical compounds that can serve as successful drugs. Nevertheless, the study shows that a large pool of potential drugs is available to cope with the parasite’s phenomenal versatility in learning to resist all of the drugs that have been thrown at them [17].

At this juncture, it is worth turning to our cousins, the chimpanzee, for guidance. The chimpanzee was observed to ingest mouthfuls of leaves from the plant Trichilia rubescens followed by mouthfuls of soil.  The herb is known to contain anti-malarial compounds, while soil particles stick to the anti-malarial compounds from the leaves and thus concentrate them.  Like artemisinin, the plant compounds may prove valuable in treating human malaria [18].

Updating malarial vaccines

RTS,S is the world’s most advanced malaria vaccine candidate against P, falciparum [2]. It is a recombinant yeast-expressed subunit vaccine that uses the hepatitis B surface antigen as a matrix carrier for epitopes derived from the circumsporozoite (CS) protein of P. falciparum. RTS,S is formulated in a proprietary adjuvant system that includes a vehicle and two immunostimulants (MPL and QS21). The vaccine has been studied in more than 4 000 subjects, including both malaria-naive and malaria-experienced adults, as well as young children and infants in malaria-endemic settings. The vaccine is produced by GlaxoSmithKline corporation (GSK) with help from Walter Reed Army Institute of Research (WRAIR) and by Infectious Diseases Development, Bill & Melinda Gates Foundation. The vaccine has been advanced to the phase III clinical trial, the last phase before licensing [19]. Under current plans, the RTS,S vaccine candidate would be submitted to regulatory authorities in 2012 based on efficacy in children 5 to 17 months of age. Additional safety and immunogenicity data from the infant population will be submitted soon thereafter, followed by efficacy data for infants once available. Depending on the final clinical profile of the vaccine and the timetable of the regulatory review process, the first vaccine introduction could take place over the next three to five years [20]. We have criticized this vaccine based on the unacceptably high adverse impacts on infants and children during previous clinical trials and the low effectiveness of the vaccine [2].  Given the clear effectiveness of ACTs in treating malaria those children contracting malaria during the course of the trials should be treated promptly with ACTs to insure their recovery from the disease.

Attenuated whole parasite malaria vaccines that confer high-level, long-lasting protection against P. falciparum, the parasite responsible for most of the malaria associated severe illness and death worldwide have been produced by the Sanaria Company of Maryland, USA. Sanaria's vaccine manufacturing process begins with hatching and rearing uninfected mosquitoes. The mosquitoes are allowed to feed on blood containing P. falciparum malaria parasites. After that, the mosquitoes are irradiated to weaken (attenuate) the parasite. Special equipment and processes are employed to harvest large numbers of the attenuated parasites from the salivary glands of the mosquitoes. The parasites are at the stage known as sporozoites. Though attenuated and unable to cause disease, the irradiated sporozites remain biologically active and are placed in vials and stored at low temperature. Purified attenuated parasites are used to produce  the malaria vaccine.  The attenuated parasites invade host tissues, but cannot complete differentiation and therefore do not replicate or cause disease.  Sanaria has built a facility to manufacture a radiation attenuated sporozoite vaccine that can be administered by injection and has met FDA regulatory standards for initial clinical evaluation. This vaccine candidate, the SanariaTM PfSPZ, has been tested on human volunteers and  is now being assessed in clinical trials   [21]. The Sanaria project has been supported by the Gates Foundation, and the Sanaria vaccine will soon be tested in phase III trials prior to commercial release.

P. falciparium vaccine candidates have been produced by the Seattle Biomedical Research Institute using a molecular genetics technique called gene knockout. Two genes needed for maturation of the parasite in the liver are deleted from the genome of the parasite. The knockout parasite strains show normal infection and elicit a strong immune response, but do not induce disease symptoms in treated animals and human volunteers [22]. The live attenuated parasite vaccines may provide complete and long lasting defence against malaria but that optimistic prognosis remains to be verified.

Insecticides in sleeping nets

Three insecticides – the pyrethroid deltamethrin, the carbamate carbosulfan and the organophosphate chlorpyrifos-methyl – were tested on mosquito nets in experimental huts to determine their potential for controlling malaria. Their effects were examined on Anopheles gambiae Giles s.s. (Diptera: Culicidae) and Anopheles funestus Giles s.s. in Muheza, Tanzania, and on Anopheles arabiensis Patton and Culex quinquefasciatus Say in Moshi, Tanzania .The rank order of the insecticides for blood-feeding inhibition (reduction in the number of blood-fed mosquitoes compared with control) for wild A. gambiae and A. funestus was deltamethrin > chlorpyrifos-methyl > carbosulfan. Deltamethrin reduced the proportion of insects engaged in blood-feeding, probably as a consequence of contact irritancy, whereas carbosulfan seemed to provide personal protection through deterred entry or perhaps a spatial repellent action. Carbosulfan deterred anophelines from entering huts. Chlorpyrifos-methyl was inferior to deltamethrin in terms of mortality and blood-feeding inhibition and would be better deployed on a net in combination with a pyrethroid to control insecticide-resistant mosquitoes [23]. A fungus pathogenic to insects, Metarhizium anisopliae, has proven effective in controlling anopheline mosquitoes [24]. The fungus may prove effective in controlling mosquitoes not only in huts but in villages and cities. Insect resistance, like parasite drug-resistance, is a constant problem in preventing malaria. The fungal insecticides appear to be an attractive substitute for chemical insecticides.

Transgenic malaria resistant mosquitoes

We first reviewed the use of transgenic mosquitoes in 2001, when they appeared ready to be released in the field [1]. But alas, they have yet to leave the confines of the laboratory, and may not do so until well after malaria has been eradicated. The use of genetically engineered mosquitoes to eradicate the parasite bearing mosquitoes needs a fuller discussion and will be the focus of a following report, Genetic Approaches to Controlling Malaria Mosquitoes.

Article first published 07/06/10

---

References

1. Cummins  J and Burcher S. Two takes on malaria: Transgenic mosquitoes coming, and Rolling back malaria i-sis news13/14, 28-29, 2002.
2. Ho MW and Cummins J. Malaria vaccine trials  raise concerns over fisks to infants Science in Society 42, .37-39, 2009.
3. Mendis K, Rietveld A, Warsame M, Bosman A, Greenwood B, Wernsdorfer WH. From malaria control to eradication: The WHO perspective. Trop Med Int Health. 2009 14(7), 802-9.
4. Wikipedia Artemisinin 2009 http://en.wikipedia.org/wiki/Artemisinin
5. World Health Organization  WHO calls for an immediate halt to provision of single-drug artemisinin malaria pills 2006 http://www.who.int/mediacentre/news/releases/2006/pr02/en/index.htm
6. Ferreira JF, Luthria DL. Drying affects artemisinin, dihydroartemisinic acid, artemisinic acid, and the antioxidant capacity of Artemisia annua L. leaves. J Agric Food Chem. 2010 Jan 5. [Epub ahead of print]DOI: 10.1021/jf903222j
7. Kumar N, Singh R, Rawat DS Tetraoxanes: Synthetic and medicinal chemistry perspective. Med Res Rev. 2009 Dec 21. [Epub ahead of print] DOI 10.1002/med.20189
8. Butler D. Malaria drug-makers ignore WHO ban. Nature News 2009, 460, 310-1.
9. Leslie T, Kaur H, Mohammed N, Kolaczinski K, Ord RL, Rowland M. Epidemic of Plasmodium falciparum malaria involving substandard antimalarial drugs, Pakistan, 2003 Emerg Infect Dis. 2009 Nov;15(11):1753-9.
10. Moon S, Pérez Casas C, Kindermans JM, de Smet M, von Schoen-Angerer T. Focusing on quality patient care in the new global subsidy for malaria medicines. PLoS Med. 2009. 6(7), e1000106.
11. Eastman RT, Fidock DA. Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nat Rev Microbiol. 2009, 7(12), 864-7.
12. World Health Organization World Malaria Report, Geneva, 2008.
13. Picot S, Olliaro P, de Monbrison F, Bienvenu AL, Price RN, Ringwald P. A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria. Malar J. 2009, 4, 8-89
14. Wells TN, Alonso PL and Gutteridge WE. New medicines to improve control and contribute to the eradication of malaria  Nat Rev Drug Discov. 2009, 8(11), 879-91.
15. Olliaro P and Wells TN. The global portfolio of new antimalarial medicines under development. Clin Pharmacol Ther. 2009, 85(6), 584-95.
16. Mazier D, Rénia L and Snounou G. A pre-emptive strike against malaria's stealthy hepatic forms. Nat Rev Drug Discov. 2009. 8(11), 854-64.
17. Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF. Thousands of chemical starting points for antimalarial lead identification. Nature 2010 465, 305-10.
18. Klein N, Fröhlich F and Krief S. Geophagy: soil consumption enhances the bioactivities of plants eaten by chimpanzees. Naturwissenschaften 2008, 95(4), 325-31.
19. Ballou WR The development of the RTS,S malaria vaccine candidate: challenges and lessons. Parasite Immunol. 2009, 31(9), 492-500.
20. GLaxoSmithKline  Malarai Vaccine Initiative Fact sheet: Phase 3 trial of RTS,S 2009 http://www.malariavaccines.org/files/05272009_Phase_3_Fact_Sheet_FINAL.pdf
21. Hoffman SL, Billingsley PF, James E, Richman A, Loyevsky M, Li T, Chakravarty S, Gunasekera A, Chattopadhyay R, Li M, Stafford R, Ahumada A, Epstein JE, Sedegah M, Reyes S, Richie TL, Lyke KE, Edelman R, Laurens MB, Plowe CV, Sim BK. Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria. Hum Vaccin 2010, 6(1), 97-106
22. VanBuskirk KM, O'Neill MT, De La Vega P, Maier AG, Krzych U, Williams J, Dowler MG, Sacci JB Jr, Kangwanrangsan N, Tsuboi T, Kneteman NM, Heppner DG Jr, Murdock BA, Mikolajczak SA, Aly AS, Cowman AF, Kappe SH. Preerythrocytic, live-attenuated Plasmodium falciparum vaccine candidates by design. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13004-9
23. Malima RC, Oxborough RM, Tungu PK, Maxwell C, Lyimo I, Mwingira V, Mosha FW, Matowo J, Magesa SM and  Rowland MW. Behavioural and insecticidal effects of organophosphate-, carbamate- and pyrethroid-treated mosquito nets against African malaria vectors. Med Vet Entomol. 2009, 23(4), 317-25.
24. Mnyone LL, Russell TL, Lyimo IN, Lwetoijera DW, Kirby MJ, Luz C. First report of Metarhizium anisopliae IP 46 pathogenicity in adult Anopheles gambiae s.s. and An. arabiensis (Diptera; Culicidae). Parasit Vectors 2009, 2(1), 59.