Principles of malaria transmission
Malaria is spread among people by mosquitoes belonging to the genus Anopheles. The female mosquito is infected by gametocytes, the sexual stages of the malaria parasite, when they take a blood meal from an infected person. Male and female gametocytes then fuse to form zygotes (ookinetes), which embed in the gut wall as oocysts and then undergo further development in the insect for 6–12 days. The mature oocysts rupture to liberate motile sporozoites, which migrate to the mosquito salivary glands to await inoculation into humans through the bite of the mosquito carrying them (1).
The intensity of malaria transmission in an area is the rate at which people are inoculated with malaria parasites by infected mosquitoes. It is expressed as the annual entomological inoculation rate (EIR), which is the number of infectious mosquito bites received by an individual in 1 year. The EIR determines to a large extent the epidemiology of malaria and the pattern of clinical disease in an area. The upper end of the EIR range is found in a few parts of tropical Africa, where rates of 500–1000 can be reached (2). At the lower end of the range, EIRs of ⩽ 0.01 are found in the temperate climates of the Caucasus and Central Asia, where malaria transmission is only barely sustained. Between these extremes are situations of unstable seasonal malaria, such as in much of Asia and Latin America, where the EIRs are < 10 and often 1–2, and situations of stable but seasonal malaria, as in much of West Africa, where the EIR is 10–100.
The proportion of infected mosquitoes in a locality reflects the capacity of the vectors to transmit malaria (vectorial capacity) and the number of infected and infectious humans in the area. Lowering the infectivity of infected persons to mosquito vectors contributes to reducing malaria transmission and eventually to reducing the incidence and prevalence of the disease. The relation between EIR and the prevalence of malaria is, however, complex: it is affected by vectorial capacity, the pattern of acquisition and loss of immunity to malaria and access to effective drug treatment in the area. The hypothetical relation represented in assumes no drug treatment. In areas of low transmission, where the EIR is < 1 or 2, a reduction in the inoculation rate will result in an almost proportionate reduction in the prevalence (and incidence rate) of malaria. When the EIR exceeds 10, there is great redundancy in the infectious reservoir, and larger reductions in transmission are required to make a significant impact on malaria prevalence. Experience with major interventions, such as use of insecticide-treated nets and artemisinin-based combination therapy, suggests that effective transmission-reducing interventions reduce mortality and even morbidity in most situations (1–4).
Relation between entomological inoculation rate and parasite prevalence (on the assumption that no infections are treated).
Effect of medicines on malaria transmission
Medicines can reduce malaria transmission by two mechanisms (5): early, effective treatment and reducing infectivity.
Early, effective treatment of a malaria blood infection with any antimalarial medicine will reduce gametocytaemia by eliminating the asexual blood stages from which gametocytes derive. The faster the clearance of asexual blood parasites, the greater the reduction in infectivity. The potent anti-infective properties of artemisinins result partly from rapid clearance of parasites. In P. vivax, P. malariae and P. ovale infections, gametocytes are susceptible to all the antimalarial drugs, have a short developmental period (2–3 days) and have short-lived mature gametocytes. Effective treatment of the asexual blood infection alone abolishes infectivity to mosquitoes. In P. falciparum infections, gametocytes take longer to develop (7–10 days), and for most of this time they are sequestered in the microcirculation (particularly in the bone marrow and spleen). Treated P. falciparum infections may remain infectious for more than 1 week after patients have been successfully treated unless they also take a specific anti-gametocyte medication (primaquine, see below).
Infectivity can be lowered either by a direct effect on gametocytes (gametocytocidal effect; primaquine) or on the parasite developmental stages in the mosquito (sporontocidal effect; antifols, atovaquone) or by killing feeding mosquitoes (endectocidal effect; avermectins). The antimalarial drugs used to treat the asexual stages of P. falciparum do not reduce the infectivity of mature infective gametocytes (3–5). Sulfadoxine–pyrimethamine in fact increases gametocyte carriage, but it also reduces the infectivity of drug-sensitive parasites. Artemisinins are the most potent gametocytocidal drugs of those currently used to treat acute malaria (6–11). They kill young gametocytes, preventing new infective gametocytes from entering the circulation, but they have less effect on mature gametocytes that may be present in the circulation at the time of treatment (6). The 8-aminoquinoline primaquine acts on mature gametocytes rapidly, reducing their transmissibility to mosquitoes and accelerating gametocyte clearance (12–20). Thus, addition of primaquine to ACTs in the treatment of P. falciparum infections rapidly and potently reduces the transmissibility of the treated infection ().
Dose–response relations for primaquine in reducing the infectivity of Plasmodium falciparum-infected individuals to anopheline mosquitoes.
Pooled data from all studies conducted (17). Vertical axes show the proportions of fed anopheline mosquitoes that were infected. Oocyst formation (upper graph) and sporozoite formation (lower graph) assessed from blood sampled 48 h after a dose of primaquine. Primaquine given with an artemisinin derivative is shown in green, and primaquine given with no antimalarial medicine or a non-artemisinin derivative is shown in red. In these studies, 29 patients received no primaquine. The size of the circle is proportional to the number of patients in each group (shown within). Corresponding adult primaquine doses are indicated in squares.
In areas of low-to-moderate transmission
The most direct consequences of lowering parasite infectivity by the use of medicines are seen in areas of low transmission, where symptomatic patients contribute significantly to the infectious reservoir. Reducing infectiousness has a significant impact on malaria transmission and thus the prevalence of infection and the incidence of disease.
In areas of high-transmission
In high-transmission areas, infected but asymptomatic people constitute an important part of the infectious reservoir. Even though treated cases (mainly children) have higher densities of gametocytes and infectivity is positively related to gametocyte density, symptomatic patients comprise only a minority of the infective reservoir (21–23). In high-transmission settings, a considerable reduction in transmission rates is required to reduce parasite prevalence (and incidence of disease). Adding transmission-blocking drugs to antimalarial treatment is not cost–effective. As malaria control intensifies in highly endemic countries, however, transmission rates are declining; infectivity-reducing drug regimens may therefore further reduce transmission and play an important role in sustaining achievements.
Thus, the use of antimalarial medicines specifically to reduce infectivity:
Strategies to reduce the transmission of drug-resistant parasites
Continued use of an antimalarial drug to which parasites are partially resistant will confer a selective advantage to resistant parasites and favour their transmission. In the presence of the drug, partially resistant infections are accompanied by more gametocytaemia than those that are sensitive (6, 7, 24). Furthermore, drug resistance leads to recrudescence associated with higher rates of gametocyte carriage than primary infections. Thus, cumulatively drug-resistant infections generate more gametocytaemia and therefore greater transmission potential than sensitive ones (25, 26). Secondly, under some circumstances, gametocytes carrying resistant genes may be more infectious to mosquitoes, producing greater numbers of oocysts and infecting a higher proportion of mosquitoes than those carrying sensitive genes (27). There is some evidence that mosquito control measures preferentially eliminate drug-resistant parasites (28). This evidence is supported by field experience in:
Zimbabwe, where house spraying with insecticides to reduce malaria transmission was associated with a decrease in drug resistance (
29), and
focal regions in India and Sri Lanka, where a combination of intense vector-control measures and switching to an effective medicine led to significant reductions and, in some instances, even elimination of chloroquine-resistant P. falciparum from those foci.
As one of the earliest features of drug resistance is increased gametocyte carriage, addition of a transmission-blocking drug such as primaquine will negate this transmission advantage and slow the spread of resistance.
Summary and conclusions
Antimalarial medicines play an important role in reducing malaria transmission and in curtailing the spread of drug-resistant parasites. Good access to diagnosis and early, effective treatment will reduce malaria transmission. Antimalarial medicines with specific gametocytocidal activity (e.g. artemisinin derivatives, primaquine) will reduce falciparum malaria transmission even further, particularly in areas of low transmission.
