Perspective on Malaria Eradication: Is Eradication Possible without Modifying the Mosquito?

In the fall of 2007, when Melinda Gates proposed to the malaria community that we consider eradication as a goal [1], many of us who had been in the malaria field for some time were shocked. We simply could not understand how malaria eradication was feasible, particularly in Africa. Although there has been encouraging recent progress in reducing disease through drugs and insect control mechanisms and in vaccine development, eradication is a different story. To a large part, our pessimism that malaria can be eradicated comes from an appreciation of the extraordinary effectiveness of the African mosquito, the Anopheles gambiae complex, in transmitting malaria. These mosquitoes are capable of spreading malaria from a single infected individual to hundreds of others. Indeed, wherever A. gambiae has been introduced outside of Africa, malaria epidemics have followed, as in Brazil in the 1930s [2]. However, taking Bill and Melinda Gates’ challenge to heart and considering it seriously, we have come to the conclusion that eradication just might be possible, but only if a new set of tools are developed that focus on reducing the effectiveness of the mosquito vector. For smallpox, an eradication success story, a vaccine was the only tool necessary, along with strong epidemiologic evidence that stopping the spread of the virus required only vaccinating around each new case. For polio, which appears to be well on its way to eradication, the only tool necessary was, again, a vaccine. Could a vaccine alone eradicate malaria? The goal of most malaria vaccine development efforts is to reduce disease and death, not to eradicate the parasite. A vaccine used in combination with antimalaria drugs and vector control could be quite effective in reducing the disease burden. However, eradication is a different story. We would argue that, in addition to vaccines, antimalarial drugs, and presently available vector control methods, eradication will require special tools that we have yet to develop. Acquiring such tools will demand a long-term commitment to research and development, and if we are to be successful, we must begin now. Even if the big 3 in malaria control—vaccines, antimalarial drugs, and insecticides/bed nets—are more effective than we could hope in terms of reducing the burden of malaria, a single infected individual and the A. gambiae mosquito would ensure epidemic spread of malaria. Polio eradication is built on the premise that vaccinated individuals will stop shedding the virus because a vaccine-induced antibody response would neutralize poliovirus in the bowel. Indeed, eradication of polio is occurring in environments in which people drink contaminated water. Malaria is a completely different story. Individuals in countries where malaria is endemic become immune to disease as they approach adulthood, but they do not become immune to infection and continue to carry malarial parasites. These asymptomatic adults are able to infect mosquitoes and transmit the parasite [3]. A vaccine that would induce sterile immunity or immunity to infection is theoretically possible, although it would require a vaccine to accomplish what natural infection is unable to do. Not a very hopeful proposition. Currently, additional efforts are working toward developing transmission-blocking vaccines that are aimed at generating antibodies to parasite proteins expressed only in the mosquito host. Unfortunately, such vaccines would not be useful for malaria eradication, because they do not eliminate infection in the human host, especially in areas of high transmission, and if transmission-blocking immunity is incomplete, mosquitoes can be infected. The new effective antimalarial therapy, artemisinin derivatives combined with other drugs (artemisinin combination therapy), is designed to treat disease and, also, in the case of artemisinin derivatives, to destroy mature Plasmodium falciparum gametocytes, eliminating transmission of the parasites to mosquitoes. Although these drugs greatly reduce disease severity in treated individuals [4] and eliminate transmission from these individuals, the adult population still carries the infection asymptomatically and transmits the parasite. Explosive epidemics are also possible when drug resistance emerges, as seems inevitable. Is there a drug that could be given to the entire at-risk population to eliminate infection and transmission? Again, it is theoretically possible, but there would be enormous selective pressure for drug resistance, and with the large number of people that would need to be treated, the probability of noncompliance would be high. Are the present vector control methods likely to eradicate malaria? A. gambiae is a “super vector” for malaria, having a long life span, feeding primarily on humans, and being highly susceptible to infection. Vector control was the centerpiece of the failed attempt to eradicate malaria in the 1950s. The 2 mosquito control methods that are presently available are insecticide-treated bed nets and insecticide spraying (using DDT, for example) to kill mosquitoes that come into houses to feed. Insecticide resistance acquired by the mosquito is a problem. Mosquitoes have also been shown to change their behavior—for example, by avoiding sprayed walls or insecticide-treated bed nets. Even though the numbers of mosquitoes are greatly reduced in homes with insecticide-treated bed nets, transmission can occur outside the homes as people visit with neighbors and friends. Taking all of this into consideration, we consider it unlikely that malaria can be eradicated using only 3 tools: vaccines, drugs, and insecticides/bed nets. For a combination of 2 of these tools—namely, drugs and insecticides—the experiment has been tried and has failed [5]. Highly effective antimalarial drugs given to the population every 2 weeks and insecticides sprayed on the walls of houses could not eliminate transmission of P. falciparum by A. gambiae in Garki, Nigeria. Malaria has only been eliminated in island communities and in parts of the world that have highly developed public health systems. Moreover, malaria has not been eliminated in areas where the A. gambiae complex is the vector, with one exception—in northeast Brazil, where A. gambiae was accidentally introduced in the 1930s. To achieve the lofty goal of eradication, we see only one path to success. We need to develop methods to modify mosquitoes so that they are unable to act as vectors of malaria and to introduce this modification into multiple mosquito populations. As far as we know, P. falciparum infections of mosquitoes offer no benefit to the mosquitoes, making the generating of refractory mosquitoes easier. In addition, there is a significant advantage of attacking the parasite in the mosquito host. In the mosquito, the parasite goes through a bottleneck that greatly reduces the number of parasites, making the probability of selecting a mutant parasite low. One might argue, as for drugs, that parasites can evolve to escape a refractory mosquito. However, Aedes aegypti and Culex quinquefasciatus have fed on infected people over millennia and have never become infected with mammalian Plasmodium organisms, despite the fact that they transmit avian Plasmodium organisms. We will need a number of advances to be able to modify mosquitoes, including a means for easy introduction of foreign DNA into mosquitoes to allow experiments to be conducted, to determine ways to eliminate the parasite in the Anopheles host and methods to transfer the refractory mechanisms into multiple mosquito populations. A Vector Biology Network that was started to approach these goals was funded by The MacArthur Foundation but was in existence for only 10 years from 1990 to 2000 [6]. At present, it would seem that malaria vector research is underfunded. Isaac Newton, despite his great accomplishments wrote, “To myself I am only a child playing on the seashore, and diverting myself in now and then finding a smoother pebble or a prettier shell than ordinary, while the great ocean of truth lay all undiscovered before me” [7]. Discovering the truths necessary to reduce the effectiveness of the mosquito vector will require attracting the brightest basic insect biologists to enter the field and long-term financial support. Such long-term commitment requires funding modes different from the typical 3- to 5-year grants. Smoother pebbles and prettier shells will not be enough. Both public institutions and private foundations will need to take on the risk of these long-term goals and support a new field in vector biology to develop the tools for malaria eradication. With such an effort, we can just see how eradication might be an achievable goal.