The Jeremiah Metzger Lecture: New Additions to The Toolbox For Global Malaria Eradication

INTRODUCTION

Malaria parasites are thought to have killed more human beings throughout history than any other single cause. Plasmodium falciparum, the most common and most deadly of the five human Plasmodia, frequently causes severe illness, expressing its own proteins on the surface of host erythrocytes. Infected red blood cells adhere to the vascular endothelium in infected tissues, including the brain in cerebral malaria, a potentially fatal form of the disease that especially afflicts young children in Africa. Although it is rapidly curable with antimalarial drugs, and preventable through chemoprophylaxis and preventing mosquito bites, malaria is estimated to kill between 600,000 and 1.2 million people every year, adding up to about 100 deaths per hour worldwide (1).

In addition to P. falciparum, the somewhat less malignant species P. vivax, ovale and malariae also contribute to the malaria burden. Hundreds of animal Plasmodia infect birds, reptiles, rodents, primates, and other non-human mammals. One of these animal malarias, P. knowlesi, long known to infect rhesus monkeys, was recently found to also cause human disease when molecular testing revealed that clinically atypical malaria attributed to P. vivax was actually caused by the morphologically similar monkey parasite (2). The following discussion will focus on P. falciparum as the primary target for malaria eradication.

THE FIRST GLOBAL MALARIA ERADICATION CAMPAIGN

Malaria was eliminated from the United States in the middle of the last century, despite having been prevalent in as many as 39 states in the 1880s, with a range spanning from Florida to Texas to Montana to Massachusetts, sparing only the states west of the Rocky Mountains except California. Malaria elimination in the US is attributed mainly to improved living standards rather than to any specific antimalaria intervention. In contrast, a prolonged campaign was required to eliminate malaria from southern European countries such as Italy, where large areas of the country once reported more than 100 annual malaria deaths per 100,000 inhabitants (3).

The availability of two inexpensive and highly effective tools accounted for these early successes in malaria elimination: treatment and prevention with the antimalarial drug chloroquine, and indoor residual spraying with the insecticide dichlorodiphenyltrichloroethane (DDT). Based on good results with the use of these tools in places with relatively strong public health and social systems such as Italy and the former Soviet Union, in 1958 the World Health Organization (WHO), with financial support and leadership from the US, embarked on an audacious campaign to rid the entire world of malaria. Now often described as a failure, this global malaria eradication campaign can fairly be viewed as at least partially successful. Although global eradication was not achieved, regional elimination was, with very substantial shrinking of the world malaria map. After millennia of no change in the global distribution of malaria, the parasite was eliminated from North America, southern Europe, and vast areas of the USSR and China. Many North African, Central and South American and Asian countries, while not achieving malaria-free status, nevertheless substantially reduced the malaria burden within their borders.

The first global malaria eradication campaign was, however, not without its setbacks and outright failures. Partly as a result of injudicious use of chloroquine, including ill-advised schemes such as distributing chloroquinized salt in the Amazon and in western Cambodia, chloroquine-resistant P. falciparum emerged in these locales and then spread globally (4). Similarly, DDT intended for spraying the insides of homes was diverted into the agricultural sector, resulting in both the evolution of insecticide-resistant mosquitoes and adverse environmental effects. A certain arrogance can be detected in the writings of malaria eradication leaders of the time, who thought that there was nothing more to be learned from studying the biology or epidemiology of malaria, its mosquito vectors, or the interactions between parasites, mosquitoes and humans, and that all that was needed was the will and the resources to apply the knowledge and tools at hand (5).

The result of this hubristic underestimation of malaria's resilience and elasticity was that, despite the successes along the edges of the malaria map, the malaria situation in sub-Saharan Africa was ameliorated virtually not at all, and in other areas where progress had been made, exhaustion of will and resources was followed by devastating rebounds in malaria. For example, the malaria eradication campaign resulted in a 1500-fold decrease in reported malaria cases in India between 1947 and 1961, from 75 million to just fewer than 50,000. By 1965 the number of cases crept back up to 100,000, and 10 years later it was back to 6.5 million. Meanwhile, malaria research had been so badly neglected that no new tools were on the horizon, leading to the trope that the malaria eradication campaign had succeeded not in eradicating malaria but in eradicating malariologists.

The effective abandonment of malaria eradication in 1969 was followed by another era of stagnation, with very little change in the global malaria burden. No longer was interrupting malaria transmission the goal—instead, for the next 3 decades the focus was shifted to preventing disease and death through case management and interventions targeting the most vulnerable groups, namely infants, young children, and pregnant women in Africa. During the time that I trained as a malariologist in the 1980s and 1990s, it was widely assumed that the overwhelming force of malaria infection felt all throughout sub-Saharan Africa was a permanent condition, and that the best we could hope to do was to help afflicted populations survive long enough to develop immunity after years of heavy, repeated exposure to malaria.

This hard won naturally acquired immunity is partial and short-lived, resulting in protection against clinical malaria disease but not infection, and lasting only a few years after the last exposure. A malaria vaccine that could provide better protection more quickly was thought to be a very long shot, and much of the research effort during the post-eradication effort was aimed at developing new drugs to replace those lost to resistance. As each new drug fell more rapidly than the last, a sense of resignation, if not despair, set in.

A NEW CALL FOR ERADICATION

How, then, did the outlandish notion of eradication get back on the table? Starting in the first years of the 21st century, a few encouraging developments began to engender a new sense of optimism. Two new tools were developed: the artemisinin antimalarial drugs, based on ancient Chinese herbal treatments, were found to be highly efficacious against multidrug-resistant malaria. Following the lead of combination therapy for tuberculosis and HIV, artemisinin-based combination therapies (ACTs) were developed and introduced (6). Around the same time, long-lasting insecticide-impregnated bed nets were shown to significantly reduce all-cause child mortality in high transmission areas (7). Led largely by the US, and in parallel with scaling up of antiretroviral therapy for HIV, the world community began to commit the resources needed to disseminate bed nets, ACTs, and rapid diagnostic tests for malaria. Global funding for malaria control ballooned from approximately $100 million in 2003 to nearly $1.5 billion in 2009. Much of the support for these efforts came from the Global Fund for AIDS, Tuberculosis and Malaria and the US President's Malaria Initiative, started by President George W. Bush, who also started the US President's Emergency Plan for AIDS Relief. These Presidential initiatives were accompanied by a groundswell of public interest that soon grew to include celebrities like Madonna, Bono, and George Clooney, who in 2011 answered readers' questions on malaria in The New York Times.

Deployment and scaling up of nets and ACTs gradually contributed to large reductions in malaria cases and deaths, even in many sub-Saharan African countries where the problem had been so intractable. At the same time, malaria research underwent a renaissance fueled by President Bill Clinton's doubling of the budget of the National Institutes of Health and championed by then NIH Director Harold Varmus, who had seen malaria in Africa before embarking on his career in cancer genetics and who helped spearhead the creation of a new international Multilateral Initiative on Malaria in Dakar, Senegal, in 1997. By 2007, the landscape had changed so much that Bill and Melinda Gates were inspired to issue a call for a renewed global malaria eradication campaign (8). Although the WHO immediately joined in the call for eradication, at the time the idea was considered to be so audacious, if not ignorant, that eradication was sometimes referred to as “the ‘E’ word.”

Malaria eradication has now been almost universally embraced, at least as an aspirational goal, and by 2009 about one third of the world's malaria endemic countries were actively engaged in eliminating malaria. Malaria elimination will no doubt be achieved by increasing numbers of countries situated around the periphery of the world malaria map, but global malaria eradication remains a distant and extremely difficult goal. With enough resources, elimination can be achieved with current tools in countries with reasonably intact economies, infrastructure, and health systems. However, global eradication means the complete interruption of transmission and elimination of every human malaria infection, including in the poorest, most war-torn, and remote corners of the world. The most effective approach for eliminating malaria has been proven to be economic and social development, which is likely to be a long time coming to malaria zones like the Democratic Republic of Congo or the Golden Triangle of Laos, Thailand, and Myanmar (Burma).

THE SPECTER OF DRUG RESISTANCE

P. falciparum resistance to chloroquine first emerged in the late 1950s in both western Cambodia and in the Amazon, and gradually spread through most of the rest of the malaria-endemic world, and resistance to the antifolate antimalarial drugs pyrimethamine and sulfadoxine followed similar patterns (4). Examination of extended haplotypes surrounding the genes encoding resistance to these drugs showed that in each case, the major genetic form of resistance that emerged first in Southeast Asia subsequently spread through the rest of Asia and then into Africa (9–11), causing large increases in malaria hospitalizations and deaths (12).

Twenty years of increasingly widespread use of ACTs without credible evidence of artemisinin resistance led to optimism that this new class of antimalarial might be more durable than its predecessors had been. However, just as the renewed call for malaria eradication was issued, reports began to emerge of waning ACT efficacy in western Cambodia (13). Documentation of greatly prolonged parasite clearance times following artesunate therapy confirmed the presence of resistance (14,15), threatening prospects for malaria eradication, which depend heavily on the continued high efficacy of ACTs.

Surveillance for artemisinin resistance would be greatly aided by a molecular marker for artemisinin resistance. Such markers have been identified and validated for chloroquine (16) and antifolate-resistant (17,18) falciparum malaria, and used to track resistance and inform drug treatment policies (19–21). A genome-wide association study using samples and data from artesunate efficacy trials in Cambodia, Thailand, and Bangladesh identified a major locus on P. falciparum chromosome 13 associated with delayed parasite clearance (22). A gene within this region encoding a kelch protein (“K13”) was subsequently shown to be associated with artemisinin resistance in vitro as well as in several sites in Cambodia (23). Mapping of resistance throughout Southeast Asia is getting underway, based on the assumption that artemisinin resistance will spread contiguously from limited foci of origin, following the patterns established by other antimalarial drugs. However, many different artemisinin-resistant K13 mutants have already been observed, and preliminary analyses of the haplotypes surrounding K13 in resistant mutants suggest that artemisinin resistance may be arising independently in many foci, posing an even greater threat to prospects for eradication.

NEW AND BETTER TOOLS

Short of waiting for an end to global poverty and strife, malaria eradication might still be achieved with new and better tools that can be implemented everywhere, including in those areas lacking good roads and health clinics and subject to civil unrest. Approaches that have been considered include using lasers to zap mosquitoes that have ingested nanoparticles (24) and releasing genetically modified mosquitoes that are refractory to malaria (25), although it can be asked how willing malaria-endemic countries will be to permit release of genetically modified mosquitoes when some African countries have refused to accept genetically modified corn in the midst of famine. Perhaps more prosaic but more achievable new tools include drugs that can be given in a single encounter that will provide radical cure and lasting prophylaxis (26) and malaria vaccines that interrupt transmission (27,28).

MALARIA VACCINES

During a discussion of a malaria eradication research agenda (29), smallpox eradication leader D.A. Henderson pointed out that global eradication attempts have failed for hookworm, yellow fever, yaws, and malaria, and succeeded, or partially or nearly succeeded, for smallpox, polio, guinea worm, rinderpest, measles, and rubella. All of the successes but one, guinea worm, relied on a vaccine as the principal tool. None of the failed eradication campaigns relied principally on a vaccine (30). Vaccines offer great advantages as tools for eradication, chief among them the possibility of providing long-term prophylactic efficacy with one or a few encounters (28).

Early malaria vaccine testing using avian models showed promising results using killed or attenuated whole organism vaccines and powerful adjuvants [reviewed in Thera and Plowe (31)]. Protection against experimental malaria infection by the bites of infected mosquitoes was achieved in human trials by David Clyde at the University of Maryland in the early 1970s (32). This result was interpreted at the time not as a direct pathway to a whole organism malaria vaccine, but rather as proof of principle that a malaria vaccine could be developed if only the right antigen were identified. Decades of malaria vaccine development research using recombinant DNA technologies to produce sub-unit vaccines based on individual parasite proteins has resulted in one modestly efficacious vaccine, RTS,S/ASA01, which is based on T-cell and B-cell epitopes derived from the major surface protein coating the sporozoite stage of the parasite that is injected by mosquitoes and invades the liver. This leading vaccine provides around 50% efficacy against clinical malaria, but considerably less protection in the youngest children who are most vulnerable to severe manifestations of the disease (33).

Sub-unit blood stage malaria vaccines have fared even more poorly in field testing, largely owing to the extensive, in some cases extreme, polymorphism in leading blood stage antigens (34). Molecular epidemiology studies at a vaccine testing site in Mali, West Africa, revealed more than 200 variants of a leading blood stage antigen in a single rural town (35). A field trial of a vaccine based on a single variant of this antigen showed that although it provided significant strain-specific efficacy against clinical malaria caused by parasites similar to the vaccine strain with respect to key polymorphisms, overall efficacy against all parasite strains was not significant (36,37). These and earlier disappointing results from clinical trials of other sub-unit and DNA vaccines led to reconsideration of the whole organism approach pioneered by Clyde 40 years ago.

WHOLE ORGANISM VACCINES: A TOOL FOR MALARIA ERADICATION?

P. falciparum parasites grown in culture have been used to infect aseptically raised mosquitoes, and the resulting sporozoites were harvested by hand dissection of the mosquito salivary glands, purified, cryopreserved, and administered by injection to human volunteers (38). The first trial of this product, the PfSPZ Vaccine, failed to show protection against experimental malaria challenge when the vaccine was administered by subcutaneous or intradermal injection (39). However, based on the observation that immune responses were far higher in monkeys when the vaccine was given intravenously (39), a human trial using the intravenous route was recently performed that showed 100% efficacy against homologous challenge in the group receiving the highest dose (40).

Numerous hurdles remain to be overcome before a whole organism vaccine can be deployed as a tool for malaria eradication. The high degree of protection achieved in the intravenous trial required a series of five immunizations—an impractical regimen under any circumstances, but particularly unsuitable for use in remote jungles and unstable border areas that will pose the greatest challenges to malaria eradication. Moreover, the vaccine has so far only been tested against homologous challenge, providing protection against infection with the same strain on which the vaccine is based. The first field trials are now underway to ascertain the vaccine's ability to protect against genetically diverse strains found in nature. In the event that a multistrain vaccine is required to provide broad protection, sieve analyses such as those used to define the basis of strain-specific efficacy for a sub-unit malaria vaccine (37), will need to be scaled up to the genomic level to guide the development of strain-transcending whole organism vaccines.

SUMMARY

Can malaria be eradicated? Yes, but probably not in my lifetime, and not without a highly efficacious malaria vaccine that can be used in conjunction with a set of tools to interrupt malaria transmission at multiple vulnerable points in the parasite-vector-host cycle. Drug resistance remains the single greatest threat to malaria elimination efforts today, and the ability of malaria parasites to evolve resistance to vaccines should be anticipated and mitigated early in the vaccine development process (34). In the meantime, eradication is the right aspirational goal. Malaria elimination is sure to be achieved in many countries, and many, many lives will be saved, if momentum toward eradication can be sustained. The eventual success of a new global malaria eradication campaign will require research as an integral component to keep up with the wily malaria parasite's proven ability to outsmart our best tools.