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Malaria: The Deteriorating Situation

This introduction provides an overview of: (1) the global extent, causative agents, and mode of transmission of malaria; (2) the health impact of malaria on the U.S. population; (3) the economic and developmental impact of malaria; (4) current strategies for malaria control; (5) the rationale for developing a malaria vaccine; and (6) the goals and target populations of malaria vaccine efforts to date.

GLOBAL EXTENT, CAUSATIVE AGENT, AND MODE OF TRANSMISSION OF MALARIA

The global importance of malaria is immense. It is the most prevalent vector-borne disease in the world, threatening some 2,400 million people in more than 90 countries—40 percent of the world's population. Malaria is estimated to cause up to 500 million clinical cases and 2.7 million deaths each year. The vast majority of deaths occur among young children; other high-risk groups include pregnant women and nonimmune travelers, refugees, displaced persons, and laborers entering endemic areas.

The causative agents in humans are four species of Plasmodium protozoa— P.falciparum, P. vivax, P. ovale, and P. malariae. Of these, P. falciparum accounts for the great majority deaths.

Malaria is most frequently transmitted from human to human by the female Anopheles mosquito; about 60 species are possible vectors for the disease under natural conditions. Malaria can also be transmitted by blood transfusions from infected persons and through contaminated needles and syringes. Even blood donations from semi-immune persons without clinical symptoms may contain malarial parasites. In congenital malaria, infected mothers transmit parasites to their children before or during birth (Hoffman, 1996).

Life-Threatening Complications of Malaria

Cerebral malaria produces seizures and unresponsive coma (Warrell et al., 1990). These complications are most frequent among African children (with a peak incidence at 3–4 years of age), but they also occur in Southeast Asian children and among nonimmune adults. Although cerebral malaria has a substantial mortality, an



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Vaccines Against Malaria: Hope in a Gathering Storm 2 Malaria: The Deteriorating Situation This introduction provides an overview of: (1) the global extent, causative agents, and mode of transmission of malaria; (2) the health impact of malaria on the U.S. population; (3) the economic and developmental impact of malaria; (4) current strategies for malaria control; (5) the rationale for developing a malaria vaccine; and (6) the goals and target populations of malaria vaccine efforts to date. GLOBAL EXTENT, CAUSATIVE AGENT, AND MODE OF TRANSMISSION OF MALARIA The global importance of malaria is immense. It is the most prevalent vector-borne disease in the world, threatening some 2,400 million people in more than 90 countries—40 percent of the world's population. Malaria is estimated to cause up to 500 million clinical cases and 2.7 million deaths each year. The vast majority of deaths occur among young children; other high-risk groups include pregnant women and nonimmune travelers, refugees, displaced persons, and laborers entering endemic areas. The causative agents in humans are four species of Plasmodium protozoa— P.falciparum, P. vivax, P. ovale, and P. malariae. Of these, P. falciparum accounts for the great majority deaths. Malaria is most frequently transmitted from human to human by the female Anopheles mosquito; about 60 species are possible vectors for the disease under natural conditions. Malaria can also be transmitted by blood transfusions from infected persons and through contaminated needles and syringes. Even blood donations from semi-immune persons without clinical symptoms may contain malarial parasites. In congenital malaria, infected mothers transmit parasites to their children before or during birth (Hoffman, 1996). Life-Threatening Complications of Malaria Cerebral malaria produces seizures and unresponsive coma (Warrell et al., 1990). These complications are most frequent among African children (with a peak incidence at 3–4 years of age), but they also occur in Southeast Asian children and among nonimmune adults. Although cerebral malaria has a substantial mortality, an

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Vaccines Against Malaria: Hope in a Gathering Storm uncertain fraction of those who survive (approximately 10 percent) have persistent neurologic deficits at the time of hospital discharge (Carme et al., 1993). Thus, the long-term effects of cerebral malaria on central nervous system development and function (including the ability to learn) are important unresolved questions with major implications for global health and development. Severe malarial anemia produces hemoglobin levels of less than 5 grams per 100 milliliters of blood —less than one-third the normal hemoglobin (Warrell et al., 1990). Although severe malarial anemia is widely prevalent until age 3, its peak incidence occurs around 6– 7 months of age (Marsh, 1992; Miller et al., 1994). Kidney failure is a common complication of malaria infection, and a major cause of death among nonimmune immigrants (Trang et al., 1992; Warrell et al., 1990; Weber et al., 1991). HEALTH IMPACT OF MALARIA ON THE U.S. POPULATION U.S. Travelers Abroad The importance of malaria for the U.S. military is enormous. In Vietnam, for example, nearly 10 percent of soldiers had the disease in late 1965, and attack rates for some units were as high as 60 per 100 soldiers each year. Overall, malaria was the most important cause of hospitalization other than combat wounds (Neel, 1973). Peace Corps volunteers also have intense malaria exposures. During the late 1980s, drug-resistant P. falciparum infection caused serious illnesses in approximately 1,600 Peace Corps workers in West Africa alone. Finally, tourists are at increasing risk, even with short-term exposure, as demonstrated by recent reports of transit passengers being infected with malaria while waiting on planes that were being refueled in West Africa (Isaacson, 1989; Lobel et al., 1993). Over 1,000 cases of malaria are known to occur each year in tourists returning to the United States. U.S. Resident Population Malaria transmission can occur in the United States. With the return of infected veterans after World War II, the Korean War, and the Vietnam War, and the arrival of infected Southeast Asian refugees, reports have confirmed transmission of malaria by indigenous anopheline mosquitoes to U.S. residents who had never left the country (Luby et al., 1967; Maldonado et al., 1990). ECONOMIC AND DEVELOPMENT IMPACT OF MALARIA When a substantial proportion of a country's population is ill with malaria for five or six months each year, sustained economic development is very difficult to achieve. Countries thus compromised cannot easily become active trading partners with the United States, nor are they positioned to decrease their dependence on

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Vaccines Against Malaria: Hope in a Gathering Storm foreign aid. Similarly, when child survival is threatened by malaria and other infections diseases, family planning and environmental quality are simply not priorities. To address development and environmental issues on a global scale, one must first prevent death and disability from malaria and other childhood diseases in regions where death rates are high. CURRENT STRATEGIES FOR MALARIA CONTROL Drug-Based Control Strategies Although antimalarial drugs are necessary to prevent death and complications in severely ill patients, they are not sufficient for malaria control. Most developing countries recommend antimalarial treatment only for symptomatic infections, because treating all infections would produce relatively small health benefits in proportion to the cost, would exacerbate selection for drug-resistant parasites, and could impair the development and boosting of natural immune responses. Unfortunately, most antimalarials are now compromised by antimalarial resistance, including the aminoquinolines and their analogs—chloroquine, mefloquine, halofantrine, quinine, and quinidine—and the antifolates. Artemisinin offers a promising alternative approach because it is effective against P. falciparum, which is resistant to the older drugs, but there are unresolved questions about its potential neurologic toxicity (Brewer et al., 1994). Thus, antimalarial treatment is currently in disarray because of widespread drug resistance in the parasite throughout all regions endemic for malaria (Hoffman, 1996; Wernsdorfer, 1994). Vector-Based Control Strategies Because of growing antimalarial drug resistance in the parasite, more emphasis is being placed on vector control by health authorities. An important recent development is the use of insecticide-impregnated bednets and curtains. Bednets and curtains treated with insecticides such as permethrin have both insecticidal and repellent effects, and they may reduce the number of anopheline mosquitoes within houses by more than 95 percent (Doumbo et al., 1991). Their effect on the prevalence of infection has been less marked, however; several studies suggest a 40– 50 percent reduction in the prevalence of P. falciparum parasitemia (Beach et al., 1993). The impact of insecticide-impregnated bednets on mortality and the incidence of severe malaria is still uncertain and remains under study (Alonso et al., 1991; Mbogo et al., 1995). Recent reports suggest that insecticide-impregnated bednets reduce malaria mortality, but raise the possibility that their efficacy may be lower in areas with more intense transmission (Binka et al., 1996; Curtis, 1996; Nevill et al., 1996). Questions have been raised as to whether this strategy might selectively encourage the proliferation of anopheline mosquitoes that bite outside the home (and would therefore not be exposed to bednets), and whether it could shift the

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Vaccines Against Malaria: Hope in a Gathering Storm malaria mortality currently observed among young children to older children and young adults. THE RATIONALE FOR DEVELOPING A MALARIA VACCINE The rationale for accelerated development of a malaria vaccine is based on the following observations: Effective vaccines, as a group, represent the single most cost-effective public health intervention. Current methods of malaria control have limited effectiveness. Drug resistance is increasing. Scientific advances in malaria immunology and advances in vaccinology have made the development of malaria vaccines an achievable goal. Vaccines in conjunction with other measures could greatly improve the effectiveness of malaria control. GOALS AND TARGET POPULATIONS FOR MALARIA VACCINES The complex life cycle of the malaria parasite has complicated vaccine development efforts (see Hoffman 1996 for a description of the Plasmodium life cycle). Each parasite stage has different antigens that lead to protective immunity and immune responses effective against one stage (for example, sporozoites), but that generally have been ineffective against other parasite stages (such as the asexual and sexual stages). This has resulted in a rich diversity of approaches to malaria vaccine development and to multiple current vaccine candidates. Development efforts to date have focused on three vaccine types. Preerythrocytic Vaccines The rationale for a preerythrocytic malaria vaccine is to prevent bloodstream infection by stimulating an immune response to sporozoite, or liver-stage, antigens. Although these vaccines are seen to offer the best protection for nonimmune individuals such as children or foreign nationals, they may also be of value to semi-immune residents of endemic areas.

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Vaccines Against Malaria: Hope in a Gathering Storm Asexual Blood-Stage Vaccines The purpose of immunization with asexual blood-stage (merozoite) antigens is to control the magnitude of the asexual parasitemia, and thus decrease the incidence of severe disease. These vaccines are seen to be of most benefit to semi-immune, long-term residents of endemic areas, although they may also benefit nonimmunes. Sexual (Gametocyte) Vaccines These vaccines are directed toward blocking infection of mosquitoes. As a result, such vaccines would not have any effect on the clinical manifestations of malaria in an individual, but could have major impact through reducing malaria transmission, and thus malaria mortality and morbidity at the population (community) level.