Perspectives

29 September 2010Dr. Kristen Kerksiek

The malaria agenda: new hopes on the horizon

More than just a pest: Anopheles mosquitoes © CDC / James Gathany

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You think your life is crazy? Try juggling between five different tissues in two separate hosts, while reproducing both sexually and asexually in a life cycle that involves ten morphological transitions. It sounds like the invention of a very imaginative science fiction writer, but the complex life of Plasmodium, the causative agent of malaria, is a very real – and incredibly successful – creation of Mother Nature. Plasmodium parasites have left their mark on human history: malaria is described in 5000-year old Chinese texts, it plagued the ancient Egyptians (probably killing King Tut), may have contributed to the downfall of the Roman Empire, and was an important factor in a number of wars. In the early 20th century, humans started fighting back with newly developed anti-malarial drugs and insecticides, but nearly a century later the disease still threatens 40% of the world’s population and is believed to kill some 1 million people - mostly young children in sub-Saharan Africa - each year.
  

Plasmodium species that infect humans

More than 200 species of Plasmodium have been identified, but only 4 distinct species – all transmitted by mosquito species of the genus Anopheles - cause human malaria disease.

P. falciparum: widespread, primarily in tropics and subtropics; causes the most severe disease characterized by multiple days of high fever, high parasitemia, severe anemia and cerebral malaria
P. vivax: most widespread geographically, range extends into temperate areas but uncommon in Africa; can cause severe and extended (chronic) illness but rarely fatal
P. malariae: broad but spotty geographical distribution; disease usually mild but chronic, with reappearance of disease (associated with renal complications) possible decades after infection
P. ovale: primarily in tropical West Africa; causes mild malaria disease with short duration

Four species of Plasmodium cause human malaria disease, but there have been increasing reports of the transmission of malaria parasites (e.g. P. knowlesi) from nonhuman primates © CDC / Steven Glenn

It’s not that the efforts to control malaria were completely ineffective. Quite the contrary, North America and Europe have been malaria-free since the mid-1900s, and infections – and malaria-related deaths - have been reduced dramatically in most parts of the world. The early successes of the insecticide DDT and new drugs to fight disease gave wings to a Global Eradication Campaign that was initiated in 1955 but abandoned some 15 years later. In many areas, the limited ground won in the fight against malaria was quickly lost again as mosquitoes developed resistance to insecticides and Plasmodium became resistant to drugs; in malaria hotspots in sub-Saharan tropical Africa, 5–10% of individuals born today will die from malaria before the age of 5, a rate very similar to that reported a century ago. And even when it doesn’t kill, malaria devastates social and economic structures.

Although malaria is most devastating in sub-Saharan Africa and Southeast Asia, it also remains endemic in parts of Central and South America © S. Jähnichen

Despite the challenges of fighting malaria – the development of resistance, the problems in fighting such a persistent foe in remote geographical areas ravaged by poverty and war and with inadequate healthcare services– the “E” word has recently been spoken again; boosted by dramatic reductions in malaria incidence in some African countries, some are again speaking of the eradication of malaria. A control strategy based on insecticide-based prophylaxis and combination drug therapy – under the right conditions - can work! But is it enough to get rid of the disease altogether?

The Keys to Control

Reduce the risk and treat the sick: on the surface the tools for fighting malaria today look pretty similar to those used decades ago. Of course, some of the primary players have changed and the game is played a bit differently. A star in early anti-malaria efforts, the insecticide DDT has largely been replaced by other chemicals because of the damaging effects of its accumulation in animals. And in contrast to widespread environmental spraying efforts of the past, insecticide use for malaria control now focuses on indoor spraying and the distribution of insecticide-treated nets, a relatively new strategy that has resulted in impressive decreases in disease. However, the development of mosquito resistance to insecticides is a constant problem in the fight against malaria.

The DDT Debate

It won its inventor a Nobel Prize in 1948, but DDT has been banned or blacklisted in most of the world due to its environmental impact (e.g. eggshell thinning in some bird species). Some are calling for a returned acceptance of DDT for use against malaria-carrying mosquitoes; although permitted for malaria control, intense international pressure – often coupled to conditions for foreign aid – have limited its use in many countries. Some of the arguments:

Pro-DDT: very inexpensive; highly effective in some areas (resistance differs geographically); internal residual spraying (IRS) has little environmental impact; repels as well as kills mosquitoes; relatively safe (many other effective insecticides are more toxic)

Anti-DDT: impacts on human health (e.g. male infertility); very persistent (long breakdown time) in the environment and organisms (fatty tissue); use of DDT is difficult to control, i.e. insecticide for disease control could be diverted to agriculture

In some (small and peaceful) African countries, recent malaria control efforts have been incredibly successful; can major malaria hotspots such as Nigeria and the D.R. Congo follow? © IHM

Widely used antimalarial drugs – from chloroquine to sulfadoxine-pyrimethamine and mefloquine – have all had to bow to the survival skills of Plasmodium: resistance to a new antimalarial drug is usually detected within a few years of use, and widespread failure can be expected within one to three decades. Hope remains in potent and rapidly acting artemisinin, an ancient Chinese drug that fights Plasmodium via a still-unidentified mechanism that is nevertheless very different from that of other antimalarials. To thwart resistance it is used primarily in combination with other drugs (artemisinin-based combination therapies, ACTs). However, despite our best efforts, artemisinin-resistant strains of P. vivax have recently been identified in Cambodia. Resistance to malaria drugs has often appeared in this area, and there is hope that it will remain regional; its spread to larger areas and to the more deadly P. falciparum is feared, as the drug-development pipelines are far away from delivering new weapons to the malaria front.

A Jab of Hope

If insecticides and drugs remain effective and control measures are optimally applied, it might be possible to eradicate malaria with the tools at hand. But it might not. Some experts believe that only an effective vaccine can make the goal of malaria eradication a reality. Theoretically a vaccine should be possible: various immunization strategies have succeeded in inducing protection in animal models, and individuals in malaria-endemic areas, while not completely protected from infection, develop enough natural immunity to prevent severe disease and death, However, the search for a malaria vaccine has been on for decades, and the results are modest at best.

Environmental spraying of DDT was key in the success of earlier malaria control efforts, but more targeted uses of insecticides (in bed nets, indoor spraying) have also proven effective © CDC

The crazy life of Plasmodium is a nightmare for the development of an effective vaccine: the parasites express distinct antigens on different morphological forms and induce different arms of the immune system in distinct host compartments. In the blood (erythrocyte) stage, Plasmodium species are also masters of antigenic variation, altering their surface proteins to avoid immune detection. Blood-stage vaccines are nevertheless in development, but there may be more hope in vaccines that target the parasite in the pre-erythrocyte (liver stage), where little antigenic variation and lower parasite numbers are the rule. There is also an increasing interest in so-called “transmission” vaccines, which would target Plasmodium in the mosquito; the immunized host would not be protected from infection but couldn’t transmit it to others (learn more about The ‘Do Unto Others’ Malaria Vaccine dx.doi.org/10.1126/science.328.5980.847). The ultimate goal is to combine effective “treatment” and “transmission” vaccines in one attractive – and effective - anti-malaria package.
  

Finally cracked?

Plasmodium is indeed a hard nut. However, the first effective malaria vaccine may not be far away. The recombinant RTS,S vaccine targets P. falciparum sporozoites, the morphological form transferred by mosquitoes, on their way to the liver or as they mature in the liver. This pre-erythrocyte vaccine should provide protection against early stages of infection and was more than 50% effective against clinical infection in Phase II trials. It has just entered large-scale Phase III clinical trials at 11 sites in 7 African countries and could be available for targeted use in children by 2013.
(Fact Sheet from GlaxoSmithKline: www.gsk.com/media/Updated-RTSS-FactSheet-21-April-2010.pdf)

Down to the roots

After the failure of the 1955 Malaria Eradication Campaign, there was widespread resignation that malaria will be with us forever. The renewed talk of eradication surprised many, but – whether the goal can be reached or not – it has given new energy to Project Malaria. Elimination of malaria is a lofty – and costly – goal; nations will have to dig deeper into their pockets than would be required for control alone. And there is still widespread debate about the best way to accomplish eradication: from the “outside in”, starting on the less affected outer edges of regions where malaria is endemic, or by directly attacking the tropical strongholds of the disease.  

Either way, consistency with flexibility will be required. There is no right way to tackle malaria worldwide, as different regions – even individual pockets of infection – have distinct factors that enable the disease to continue its stranglehold. Action at the local level, from education to establishment of healthcare infrastructure to the determination of specific resistance patterns, will be required. Attacking the roots of malaria is the key to success in the fight against disease, and maybe, just maybe, it can enable the dream of eradication to become a reality.
  

References and further reading

Bulletin of the World Health Organization (2008): Malaria eradication back on the table. www.who.int/bulletin/volumes/86/2/07-050633/en/

Duffy, PE et al. Malaria: progress, perils, and prospects for eradication. J. Clin. Invest. (2008) 118: 1266–1276. dx.doi.org/10.1172/JCI33996

Langhorne, J et al. Immunity to malaria: more questions than answers. Nat. Immunol. (2008) 9: 725–732. dx.doi.org/10.1038/ni.f.205

Carter, R and Mendis, KN. Evolutionary and historical aspects of the burden of malaria. Clin. Microbiol. Rev. (2002) 15(4): 564–594. dx.doi.org/10.1128/CMR.15.4.564-594.2002

Science Special Issue Malaria & Tuberculosis (May 14, 2010)
Hurtley, S et al. Landscapes of Infection. dx.doi.org/10.1126/science.328.5980.841
  
  

News

Enserink, M. Redrawing Africa's Malaria Map. dx.doi.org/10.1126/science.328.5980.842
  
Enserink, M. As Challenges Change, So Does Science. dx.doi.org/10.1126/science.328.5980.843
  
Enserink, M. Malaria's Drug Miracle in Danger. dx.doi.org/10.1126/science.328.5980.844
  
Enserink, M. If Artemisinin Drugs Fail, What's Plan B? dx.doi.org/10.1126/science.328.5980.846
  
Vogel, G. The ‘Do Unto Others’ Malaria Vaccine. dx.doi.org/10.1126/science.328.5980.847
  
Roberts, L. Shrinking the Malaria Map From the Outside In. dx.doi.org/10.1126/science.328.5980.849
  
Roberts, L. Elimination Meets Reality in Hispaniola. dx.doi.org/10.1126/science.328.5980.850
  

Reviews

Kappe, SHI et al. That Was Then But This Is Now: Malaria Research in the Time of an Eradication Agenda. dx.doi.org/10.1126/science.1184785
  
Mackinnon, MJ and Marsh, K. The Selection Landscape of Malaria Parasites. dx.doi.org/10.1126/science.1185410

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