INTRODUCTION

This chapter reviews malaria control over the last century, tracking malaria's retreat from much of the world to its current lines of demarcation. It also describes individual control methods targeting both the mosquito vector and the human reservoir of infection and the current status of diagnosis and vaccine development. The chapter concludes with a discussion of malaria control strategies, including national and regional policies and programs operating today.

HISTORICAL OVERVIEW

Historically, malaria's reach extended far beyond the tropics. Until the 19th century, transmission occurred in much of the temperate world, including parts of England, Holland, Germany, central and southeastern Europe, Asia, India, China, and the Americas (Shiff, 2002). In North America, the disease reached as far north as New York, and even Montreal (Barber, 1929). In the early 20th century, the Tennessee Valley Authority brought hydroelectric power to the southeastern United States, modernizing the region. As housing and lifestyles improved, and the human reservoir of infection decreased, malaria retreated (Desowitz, 1999). Malaria also disappeared during the first half of the 20th century from most of Europe following changes in land use, agricultural practices, house construction, and targeted vector control (Greenwood and Mutabingwa, 2002).

Then came the golden days of DDT, a highly effective insecticide first used as a delousing agent at the end of World War II. During the 1950s and 1960s, indoor residual spraying with DDT was the centerpiece of global malaria eradication efforts. DDT's months-long ability to kill or deter adult female mosquitoes resting on treated walls after feeding led to further declines in malaria in India, Sri Lanka, the former Soviet Union, and other countries. By 1966, campaigns using DDT spraying, elimination of mosquito breeding sites, and mass treatment had freed more than 500 million people (roughly one-third of the population previously living in malarious areas) from the threat of disease (Shiff, 2002). Unfortunately, eradication was not sustained due to high program costs, community resistance to repeated house spraying, and the emergence of resistance to DDT. By the late 1960s, the hope of eradicating malaria through vector control was finally abandoned (Guerin et al., 2002). In many countries, the pendulum then swung to overreliance on chloroquine, a widely available antimalarial drug.

Sub-Saharan Africa was always a special case. With the exception of a few pilot programs, no sustained malaria control efforts were ever mounted there (Greenwood and Mutabingwa, 2002). The biggest obstacle was the widespread distribution of Anopheles gambiae, a long-lived and aggressive malaria vector. The entomological inoculation rate (EIR) (which measures the frequency with which a human is bitten by an infectious mosquito) rarely exceeds five per year in Asia or South America. In contrast, EIRs of over 1,000 have been recorded in several parts of sub-Saharan Africa (Greenwood and Mutabingwa, 2002).

Today, the global burden of malaria is concentrated in sub-Saharan Africa where stable, endemic disease is linked to poverty and highly efficient vectors. The insecticide-treated bednet (ITN)—first shown in The Gambia to reduce overall childhood mortality by 60 percent when combined with malaria chemoprophylaxis (Alonso et al., 1991)—is the vector control tool with the greatest promise for Africa. At the Africa Summit on Roll Back Malaria in Abuja, Nigeria in 2000, leaders from 44 African countries set a target of 60 percent ITN coverage of pregnant women and infants in Africa by 2005, an ambitious goal requiring roughly 160 million ITNs at an estimated cost of US$1.12 billion (Nahlen et al., 2003). Sadly, the goal is still far from being met. At the same time, insecticide resistance (involving pyrethroids and DDT) is a growing problem in Africa, along with environmental change brought by agriculture and other types of development that foster mosquito breeding. International sponsors also have withdrawn support for DDT due to environmental concerns.

With respect to malaria's human reservoir, the overriding challenge facing Africa is the development of drug resistance by Plasmodium falciparum to cheap and effective treatments (chloroquine and sulfadoxinepyrimethamine [SP]), compounded by large and, in some cases, mobile infected populations.

BASIC PRINCIPLES OF MALARIA CONTROL

Successful malaria control programs traditionally use multiple interventions. In 1952, Paul Russell (a noted Rockefeller Foundation malariologist, and former head of the Allied antimalaria campaign in Italy) listed five approaches to malaria eradication (Russell, 1952):

1.

Measures to prevent mosquitoes from feeding on humans (human-vector contact)

2.

Measures to prevent or reduce the breeding of mosquitoes

3.

Measures to destroy mosquito larvae

4.

Measures to kill or reduce the lifespan of adult mosquitoes

5.

Measures to eliminate malaria parasites from humans

Since Russell's era, an increasing emphasis on the control of human disease has produced three additional strategies (Beales and Gilles, 2002):

6.

Measures to prevent and reduce malaria mortality (especially in high-risk groups)

7.

Measures to reduce malaria morbidity

8.

Measures to reduce malaria transmission

Today's control efforts mainly rely upon the interruption of human-vector contact and treatment of infected persons. Personal protection via ITNs or curtains is generally preferred in settings where vectors feed indoors during nighttime sleeping hours. ITNs also kill malaria vectors and reduce the local intensity of transmission (the “mass effect”). Indoor residual spraying (IRS) with DDT or a pyrethroid insecticide is another way to reduce bites by vectors whose feeding and resting habits render them susceptible, as long as the majority of houses in a targeted community are sprayed. IRS also is the preferred vector control method during malaria epidemics and in refugee camps since trained spray teams can rapidly cover likely areas of transmission.

Case management—which encompasses prompt access to health care, an accurate diagnosis, and effective treatment—is the other cornerstone of malaria control. The current failure to control malaria with drugs often starts with a failure to deliver appropriate case management to many malaria sufferers, particularly at the periphery of health systems.

Other control strategies outlined by the World Health Organization (WHO) in 1993 include early forecasting of malaria epidemics and the development of epidemiological information systems; capacity-building in basic and applied research; and ongoing assessment of ecological, social, and economic determinants of disease within affected countries and regions (WHO, 1993). Effective field operations also require expertise and teamwork. Qualified personnel with the scientific knowledge, skills, and authority are perhaps the single most important resource needed for effective vector control (Roberts et al., 2000). The same need for knowledge applies to those rendering clinical care to malaria patients: from parents, village health care workers, drug sellers, and traditional healers to laboratory workers, nurses, doctors, and other health care professionals.

INSECTICIDES AND INSECTICIDE RESISTANCE

INSECTICIDE-TREATED BEDNETS AND INDOOR RESIDUAL SPRAYING

Individual and Community Effects of ITNs

Child Mortality

After a number of small-scale studies in the 1980s showed favorable effects, the first large-scale study of ITNs plus chemoprophylaxis reported a 60 percent reduction of all-cause child mortality (Alonso et al., 1991). These results prompted the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) to sponsor four randomized controlled trials in Africa to assess the effect of ITNs on all-cause mortality in African children in different epidemiologic settings. A cluster randomization design was used in all four trials. In The Gambia (D'Alessandro et al., 1995), a 25 percent reduction in all-cause mortality was seen in children less than 9 years old. In Kenya (Nevill et al., 1996) and Ghana (Binka et al., 1996), the introduction of ITNs was associated with 33 and 17 percent reductions in all-cause child mortality, respectively, in children under 5 years of age. Study populations in all three sites ranged from 60,000 to 120,000 (Table 8-1).

TABLE 8-1

Protective Efficacy of ITNs: Reductions in Child Mortality in Five Randomized Controlled Trials.

The fourth randomized controlled trial in Burkina Faso (Habluetzel et al., 1997) examined insecticide-treated curtains (ITCs) rather than bednets in roughly 100,000 residents of a region with alternating high and low malaria seasons. Baseline mortality, approaching 45 per thousand, was the highest to date among the four African ITN trials (Diallo et al., 1999). After 2 years of tracking, the use of ITCs was associated with a 15 percent decrease in all-cause mortality in Burkina Faso, concentrated in the first year of use.

Viewed as a group, the four TDR-sponsored randomized controlled trials demonstrate decreasing ITN efficacy with increasing transmission pressure, since sites experiencing higher EIRs (100-500 infective bites per person per year, i.e., Ghana, and Burkina Faso) witnessed lower ITN benefits.

The most recent group-randomized controlled trial of permethrin-treated bednets conducted in western Kenya (Hawley et al., 2003a) was designed to assess ITN efficacy at an upper range of year-round transmission. This study yielded an overall protective efficacy of 16 percent in all-cause child mortality; thus, ITN benefits were validated in an area of very high transmission. Maximum effect was dependent on regular re-treatment of ITNs, however. For example, the protective efficacy of ITNs in children aged 1-11 months fell from 26 to 17 percent when re-treatment was delayed beyond 6 months. The Kenyan trials also demonstrated roughly 90 percent transmission reduction from a baseline EIR of 60-300 (Gimnig et al., 2003b). When ITNs are combined with highly effective therapy such as artemisinin combination therapies (ACTs)—even in highly endemic areas— it is possible that the EIR could decline even further, approaching 0 (Personal communication, N. White, Mahidol University, February, 2004).

Child and Maternal Morbidity

Acute and chronic consequences of childhood malaria include uncomplicated febrile episodes with parasitemia, and anemia. Data from a large meta-analysis suggest that ITN use under stable transmission conditions roughly halves mild malaria episodes in children under five (Lengeler, 2001). In a nonrandomized trial of ITNs in southwestern Tanzania, treated nets conferred protective efficacy of 62 and 63 percent, respectively, on parasitemia and anemia in children under 5 (Abdulla et al., 2001). In an area of high perennial transmission in western Kenya, ITNs delayed the time to first infection in infants from 4.5 to 10.7 months (ter Kuile et al., 2003a).

Repeated malaria infection also causes anemia and morbidity in pregnant women and newborns. Four randomized controlled trials of ITNs in pregnancy have shown variable benefits in different transmission settings. In Thailand and The Gambia (areas with lower, seasonal transmission), ITNs significantly reduced malaria parasitemia and maternal anemia (Dolan et al., 1993; D'Alessandro et al., 1996); in The Gambia, they also increased birth weight (D'Alessandro et al., 1996). However, similar benefits were not seen in areas with more intense transmission (coastal Kenya and Ghana) (Shulman et al., 1998; Browne et al., 2001), raising concern that ITNs might not protect pregnant women in areas with a very high EIR. This concern was allayed by the most recent findings.

In the western Kenya trial, complete data were available in nearly 3,000 pregnancies (ter Kuile et al., 2003b). Before the study began, up to one-third of all infants were born preterm, small for gestational age, or with low birth weight. ITN-using pregnant women (gravidae 1-4) experienced a 38 percent reduction in maternal parasitemia, a 47 percent reduction in malarial anemia, and a 35 percent reduction in placental malaria at the time of delivery, while their newborns demonstrated a 28 percent reduction in low birth weight.

Community and Population Effects

In addition to conferring benefits upon individual users, ITNs can protect nonusers within ITN households as well as nonusers in nearby houses. Such effects were first noted in early village-scale ITN trials in Burkina Faso (Robert and Carnevale, 1991), Tanzania (Magesa et al., 1991), Kenya (Beach et al., 1993), and Zaire (Karch et al., 1993). More recent ITN studies have confirmed community-wide reductions in vector populations (Hii et al., 1997; Binka et al., 1998; Hii et al., 2000; Howard et al., 2000; Maxwell et al., 2002). Some ITN trial data have even demonstrated spatial effects on health. In Ghana, child mortality increased by 6.7 percent for every 100 m away from an intervention compound (Binka et al., 1998), while in western Kenya, mortality, parasitemia, and anemia decreased in unprotected children living within 300 m of households from ITN villages (Gimnig et al., 2003a). The minimum ITN coverage needed to achieve community benefits is 50 to 60 percent of households within a neighborhood with suitable indoor, night-biting vectors (Hawley et al., 2003b). In Asia, in contrast, ITNs have had mixed results because vectors often bite outdoors in the late evening (or sometimes in the early morning), and both children and adults are susceptible.

Indoor Residual Insecticide Spraying

Sprayed insecticides to kill adult mosquitoes were introduced on a large scale in the mid-1930s. Pyrethrum was first used for indoor residual spraying (IRS) in southern Africa and India and later replaced by DDT after World War II. IRS is most effective in reducing mosquitoes that rest indoors following a blood meal. To be effective, IRS does not have to kill all Anopheles at once but simply prevent a large proportion from surviving 12 to 14 days (the time it takes for a malaria parasite to develop to the infective stage within the mosquito). Even with the hardiest vectors, this can be achieved with a daily mortality of 40 to 50 percent. In places with lower malaria endemicity, daily mosquito mortality of 20 to 25 percent generally is adequate (Beales and Gilles, 2002).

Just as ITNs extend benefits to nonusers in the community, IRS is especially effective when applied on a large scale, since this maximizes the reduction in mosquito lifespan, and overall transmission. This so-called mass effect has been well documented in a number of IRS trials. Specific examples include three demonstration projects in Africa: an observational study in the Pare-Taveta Malaria Scheme in Tanzania where dieldrin reduced malaria transmission from an annual EIR of 10-50 to <1 (Pringle, 1969; Bradley, 1991); a trial in Kisumu, Kenya, where IRS with fenitrothion reduced malaria transmission by 96 percent compared to baseline over 2 years (Payne et al., 1976); and the Garki project in northern Nigeria where IRS with propoxur also substantially decreased transmission and improved infant and child mortality (Molineaux, 1985) (Box 8-1).

BOX 8-1

The Garki Project. In the early 1970s, an ambitious malaria control experiment was undertaken to determine whether malaria transmission could be interrupted in a highly endemic area of Africa. The experiment was conducted in a group of villages near the (more...)

Over the last 30 years, DDT-based IRS has declined, in part, because of DDT resistance among malaria vectors. A lack of sustained government support and financing as well as general disapproval of DDT by the international community also have contributed to IRS's restricted use in sub-Saharan Africa. In parts of Asia, Latin America, and southern and northeastern Africa where IRS is still used, it is typically organized and paid for by governments (for example, government-funded DDT house spraying was recently reinstated in KwaZulu Natal, South Africa, and the Madagascar highlands because of rising prevalence of pyrethroid-resistant A. funestus vectors and human malaria cases [Hargreaves et al., 2000]). IRS also is used in urban epidemics and refugee camps worldwide, and sometimes provided by foreign and multinational companies for the protection of employees and local communities in malaria-endemic areas (Sharp et al., 2002a).

The implementation of IRS is not trivial, and, if incorrectly performed, may be quite ineffective (Shiff, 2002). Houses and animal shelters within a target area should receive IRS before the start of the transmission season and at regular intervals thereafter. Before application of insecticide, all furniture, hanging clothing, cooking utensils, food and other items should be removed from human habitations, and left covered outside. Emulsions or solutions of insecticide are often preferred over suspensions of water-dispersible powders, which leave whitish deposits. Mud and porous plaster walls retain less IRS insecticide than wood or non-absorptive surfaces.

OTHER VECTOR CONTROL MEASURES

TREATMENT AND CHEMOPREVENTION

The primary aim of malaria treatment is saving lives. Prompt, effective treatment in the early stages of falciparum malaria reduces the risk of death as much as 50-fold, whereas effective treatment after progression to severe illness produces only a five-fold reduction in the risk of dying (White, 1999). However, malaria treatment also can reduce malaria transmission in endemic areas. This section reviews the role of treatment as a control measure capable of reducing malaria transmission, as well as past and present chemoprevention strategies in residents of malaria-endemic areas. (See Chapter 9 for more detailed information regarding antimalarial drugs, drug resistance, and treatment protocols.)

Antimalarials and Reduction of Malaria Transmission

A key objective of many early studies of widespread antimalarial distribution was interrupting malaria transmission (Greenwood, 2004). Two approaches were tried: treatment of symptomatic cases; and mass drug administration, which included mass chemoprophylaxis, and the Pinotti method—the systematic addition of antimalarial drugs to salt.

Treatment of Symptomatic Cases

The notion that treating symptomatic individuals might indirectly protect an entire malaria-exposed population dates back to Robert Koch and the early years of the 20th century (Harrison, 1978). At that time, with this goal partly in mind, quinine was used extensively in Italy and elsewhere. Since quinine has little effect on gametocytes, however, it had little effect on transmission overall.

Today, in contrast, artemisinin-based drugs (which do kill early-stage gametocytes as well as asexual parasites) have helped to decrease transmission in selected areas of Asia and Africa. On the Thai-Burmese border, where field studies using ACTs were first undertaken in 1991, replacing mefloquine with mefloquine-artesunate as first-line treatment for symptomatic malaria substantially reduced the incidence of local P. falciparum infection (Nosten et al., 2000). Widespread use of artemisinins and ACTs— along with ITNs or IRS—also contributed to a marked decline in the overall incidence of falciparum malaria in Vietnam (Hung et al., 2002) and South Africa (Barnes et al., 2003) (Box 8-2)—both areas with relatively low EIRs. Whether widespread use of ACTs will bring about a similar outcome in areas of higher malaria transmission (EIR > 100) is still unknown.

BOX 8-2

Malaria Morbidity and Mortality in KwaZulu Natal. Ingwavuma district in northern KwaZulu Natal carried the highest malaria burden in South Africa until 2000. This changed after improvements in vector control in KwaZulu Natal and neighboring southern Mozambique (more...)

Mass Drug Administration

Unlike Southeast Asia and South Africa, many malaria infections in sub-Saharan Africa—especially in older children and adults—are asymptomatic and untreated but have parasite densities sufficient for transmission (von Seidlein et al., 2002). Under these conditions, reducing malaria transmission by use of a gametocytocidal drug requires that asymptomatic as well as symptomatic carriers be treated. This led to the concept of mass drug administration (MDA). During MDA, the entire population of a community known to contain many asymptomatic infected subjects receives treatment without first determining who is actually parasitemic.

MDA as a method of reducing malaria transmission gained momentum after the 8-aminoquinolones (of which primaquine is the leading prototype) were discovered. This class of drugs is highly effective at killing gametocytes of P. falciparum. One of the first trials to investigate 8-aminoquinolones as MDA agents took place in a Liberian rubber plantation in 1930. Mass treatment with plasmoquine led to a marked decrease in parasite prevalence and a reduction in infected mosquitoes in two treated camps (Barber et al., 1932). During the 1960s and 1970s, several more MDA trials took place in Africa and Asia with the primary aim of interrupting transmission (von Seidlein and Greenwood, 2003). By today's standards, the studies were poorly designed and their results difficult to assess; however, in nearly all cases, MDA failed to interrupt transmission, although it did markedly reduce parasite prevalence (Greenwood, 2004) (Box 8-1, The Garki Project). In 1981, the largest-ever MDA program produced essentially the same outcome. After a single round of chloroquine plus primaquine was given to roughly eight million people in Nicaragua, there was an immediate, marked decrease in clinical P. vivax malaria, but transmission continued and the incidence of malaria soon returned to its previous level (Garfield and Vermund, 1983).

In most MDAs, tablets have been given, sometimes under supervision. Although this ensures effective dosing, it is onerous. As an alternative to tablets, Pinotti devised the concept of drug delivery using medicated salt (Pinotti, 1954). During the 1950s, a number of trials of medicated salt were conducted in malaria-endemic areas (Payne, 1988); they generally led to a reduced incidence of clinical episodes of malaria at the cost of rapid emergence of antimalarial resistance (Meuwissen, 1964; Giglioli et al., 1967). It is now known that exposing malaria parasites to suboptimal doses of antimalarial drugs over time is an ideal way to induce resistance. Thus, medicated salt has no place in malaria control today.

One MDA program that incorporated other control interventions was recently reported from the island of Aneityum, Vanuatu. In this case, the effort was successful. Eight rounds of MDA with chloroquine-SP-primaquine combined with ITNs and environmental control measures eliminated falciparum infection from the island (Kaneko et al., 2000).

DIAGNOSTIC METHODS

The correct and timely diagnosis of malaria is critically important to the individual patient in whom the disease may quickly progress to a life-threatening stage. Rapid diagnosis, both on an individual and a population level, also is an important tool in overall malaria control. This section reviews currently available methods of diagnosis, with emphasis on newer rapid tests that require relatively little technical expertise to perform. Such tests are now facilitating the delivery of effective treatment in a variety of low-transmission settings, and will eventually find their place in malaria case management in high-transmission settings as well.

MALARIA VACCINES

No malaria vaccine has yet entered routine use, and a safe and effective vaccine is at least another 10 years away (Greenwood and Alonso, 2002). This fact alone supports the central argument of this report, namely that a subsidy for effective treatment is an urgent priority that cannot wait until another control measure such as a vaccine is implemented. Nonetheless, the last 2 decades have seen significant progress in malaria vaccine research (Greenwood and Alonso, 2002). Highlights are summarized below.

The malaria vaccine era launched in the 1970s when, building on earlier work in rodent models, investigators at the University of Maryland demonstrated that irradiated sporozoites of P. falciparum and P. vivax protected naïve volunteers against challenge by infective mosquitoes (Clyde, 1975). For the next 2 decades, advances came mainly in experimental models rather than in human trials (Kwiatkowski and Marsh, 1997). In 1990, the first report of a vaccine field trial in an endemic area was published: a study of pre-erythrocytic vaccine in Burkina Faso (Guiguemde et al., 1990). A recent meta-analysis of malaria vaccine trials documented 18 trials with 10,971 participants using pre-erythrocytic and blood-stage vaccines (Graves and Gelband, 2003). Table 8-2 lists vaccines in field trials as of May 2003 (Moorthy et al., 2004). Additional single and combination antigens are currently in various stages of pre-clinical assessment.

TABLE 8-2

Candidate Malaria Vaccines in Clinical Trials.

A comprehensive discussion of all malaria vaccines is beyond the scope of this report; however, certain basic concepts and prototype vaccines are covered below. For further details of specific vaccine antigens and strategies, readers are directed to several excellent published reviews (Moore et al., 2002; Carvalho et al., 2002; Mahanty et al., 2003; Moorthy et al., 2004).

What Is Really Needed from a Malaria Vaccine?

Modern malaria vaccine development has followed a somewhat chance course thus far, guided by discoveries of particular antigens or enthusiasms of individual investigators (Greenwood and Alonso, 2002). However, as resources increase and more potential vaccine antigens are identified, defining the primary characteristics needed in a malaria vaccine becomes essential.

A perfect malaria vaccine would induce lifelong sterilizing immunity, provide cross-species protection, protect the very young, and be compatible with routine EPI (Expanded Programme on Immunization) vaccines. Since none of these goals will be achieved quickly, vaccine researchers are faced with a choice: either to work on a safe, highly efficacious and commercially viable vaccine (such as a pre-erythrocytic vaccine) for the short-term traveler or to work on a vaccine that offers more long-lasting protection, augmenting (as opposed to replacing) natural immunity in residents of malaria-endemic areas. For example, among semi-immune recipients, a blood-stage vaccine that lowered parasite density might prove beneficial even if it had little effect on the incidence of infection. Similarly, a partially effective preerythrocytic vaccine might protect against death from malaria just as ITNs do. Whether or not an imperfect malaria vaccine justifies use in a particular setting will depend upon its efficacy relative to other available control tools, its acceptability, and its cost.

Pregnant women in malaria-endemic areas, especially primigravidae, have a special need for enhanced malaria protection because of malaria's damaging effects in pregnancy. In some areas, it is becoming difficult to provide this protection through any other means (e.g., chemoprophylaxis, or intermittent treatment). A vaccine that prevented sequestration of P. falciparum parasites in the placenta might lessen the chance of a pregnant woman giving birth to a low-birth weight baby, but would not protect her from anemia.

Single versus Combination Candidates

For various reasons, including malaria's antigenic variation and protein polymorphisms, it is unlikely that any single malaria antigen will be found that meets all of the criteria for a perfect vaccine. Thus, the most effective malaria vaccines are likely to contain a “cocktail” of antigens from the same stage of the parasite's life cycle, or different antigens from different stages. The most extensively tested combination vaccine thus far is SPf 66, which includes several erythrocytic-stage antigens originally found protective in Colombia (Pattarroyo and Armador, 1999). However, trials using SPf66 in holoendemic areas of Africa showed marginal, if any, protection (Alonso et al., 1994; D'Alessandro et al., 1995), nor did the vaccine confer protection upon Tanzanian infants when administered as part of their initial EPI vaccine package (Acosta et al., 1999). The vaccine also failed to protect Karen children in a malarious region of northwestern Thailand (Nosten et al., 1996).

The first multistage, multiantigen P. falciparum vaccine candidate was NYVAC-Pf7, an attenuated vaccinia virus genetically engineered to include seven P. falciparum genes encoding the pre-erythrocytic antigens CSP and LSA1; the asexual blood stage antigens MSP1, AMA1 and SERA; and the transmission-blocking antigen PFs25 (Tine et al., 1996). Initial studies did not demonstrate protection against P. falciparum in human volunteers, although detectable immune responses were elicited (Ockenhouse et al., 1998). MuStDO (Multi-Stage Malaria DNA Vaccine Operation) is an ongoing collaboration involving several scientific institutions worldwide, including the Naval Medical Research Center (NMRC), the U.S. Agency for International Development (USAID), the Noguchi Memorial Institute of Medical Research in Accra, Ghana, and the Navrongo Health Research Centre in Navrongo, Ghana. Experimental development of the MuStDO vaccine is currently focused on 15 P. falciparum antigens (5 pre-erythrocytic and 10 erythrocytic proteins) (Kumar et al., 2002), although future versions also may incorporate transmission-blocking antigens.

Practical Realities of Vaccine Testing and Use

Selecting which malaria antigens should enter clinical trials was not a major problem when there were relatively few candidates to choose from. However, characterization of the P. falciparum genome has now identified hundreds of parasite proteins that could potentially be tested as individual vaccine components. Selecting future vaccine components should rest upon: 1) evidence that the antigen plays an important role in the survival or pathogenicity of the parasite; 2) evidence from animal experiments that the antigen induces protective immunity in vivo; and 3) evidence that immune responses to the antigen are associated with protection (Greenwood and Alonso, 2002). If a vaccine candidate passes Phase I and Phase II testing, further considerations in designing phase III trials include study site, study population, study size, and appropriate clinical end points (Table 8-3). Another important factor that will influence whether a partially effective malaria vaccine is introduced into routine use will be its cost effectiveness relative to other malaria control measures, such as ITNs (Graves, 1998; Goodman et al., 1999).

TABLE 8-3

Possible End Points for Phase-III Malaria Vaccine Trials.

SOURCE: Greenwood and Alonso (2002).

No matter when and where vaccination enters widescale use, it is unlikely to supplant the need for effective treatment of drug-resistant falciparum malaria for several decades (Personal communication, B. Greenwood, London School of Hygiene and Tropical Medicine, March 2004).

INTEGRATED CONTROL PROGRAMS AND SPECIAL SETTINGS

MALARIA CONTROL PROGRAMS AND DRUG POLICIES

Current Status of National Malaria Drug Policy in Africa, Asia, and South America

In 1993, Malawi was the first sub-Saharan country to switch from chloroquine to SP as first-line therapy for P. falciparum. Between 1998 and 2001, Kenya, Uganda, Tanzania, Zanzibar, Rwanda, and Burundi followed suit (like Malawi, they either chose SP monotherapy or a combination of SP plus chloroquine or amodiaquine). Countries that have now adopted and (more recently) implemented ACTs include Tanzania (Zanzibar) (2001), Zambia (2001), and Burundi (2002). In South Africa, the provinces where ACTs have been fully implemented are KwaZulu Natal (Coartem), and Mpumalanga (artesunate+SP) (WHO/UNICEF, 2003). First-line antimalarial drug policies for selected countries in Africa, Asia, and South America, as of March 2003, are listed in Table 8-4.

TABLE 8-4

Countries/Regions Using ACTs as First-Line Therapy for Uncomplicated Malaria.

CONCLUSION

In summary, as of 2004, malaria control can be viewed either as a cup half-full or half-empty. On the positive side: more money has become available for malaria control (although not nearly enough), long-lasting ITNs are finally becoming a reality, combination therapy with artemisinins is more widely available than before (although a radical solution is still needed for ACTs to reach the vast majority of malaria sufferers, especially in sub-Saharan Africa), and vaccine research is progressing. Vector control and ITNs will never have a major effect in many areas of Asia, on the other hand, because of local vector behavior; there, the main strategy must be effective treatment. And despite many earnest hopes for a vaccine solution to the world's malaria problem, vaccines are far from ready and will never control malaria by themselves—in Africa especially, there will always be a role for vector control and drugs. Improved drug delivery (including home management of severe malaria with ACTs) is another practical issue that is currently under consideration but will require even more attention after effective first-line treatments reach Africa.

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