Malaria is an acute febrile infectious disease transmitted through the bites of infected female Anophelesmosquitoes. In 2017, approximately 219 million cases of malaria were reported in 91 countries, compared with 237 and 211 million cases in 2010 and 2015, respectively. The change in the endemicity pattern is attributed to the large-scale implementation of malaria control measures, such as adequate and early treatment of patients, use of insecticide-treated nets (ITNs), and insecticide indoor residual spraying (IRS). Despite such global reductions, the case incidence substantially increased in the Region of the Americas between 2014 and 20161.
Historically, fluctuations in malaria cases in Brazil are attributed to waves of economic development; construction of railroads, highways, and other large edifice-like hydroelectric power plants (HPPs); and population displacement and land occupation policies, especially in the Northern region2–5. Consequently, vector control measures were widely used with an important role in reducing the epidemiology of malaria. Indeed, the success in the extinction of An. gambiae in the Brazilian territory is a notable outcome of such a process6–8. In this article, we reviewed the vector control measures established in the Brazilian territory.
MALARIA AND VECTOR CONTROL IN BRAZIL: A BRIEF HISTORICAL OVERVIEW
After the colonial period, there was a substantial increase in malaria cases in the Amazon region, mainly owing to the great displacement of immunologically incompetent Northeastern migrants led by rubber extraction in the Amazon (1879-1912) and the expansion and construction of the Madeira-Mamoré Railroad (1907-1912)3,9–13.
During the late 1930s, the Northeast Region of Brazil was invaded by An. gambiae, an important vector of malaria in sub-Saharan Africa later identified as An. arabiensis6. This vector was introduced accidentally in Natal, Rio Grande do Norte from Dakar (Senegal) and immediately spread to the immediate vicinity of the railway and canals near the Potengi river7,9,13,14. In 1931, 344 deaths were reported in Natal, and in 1938, it spread silently inwards, reaching less arid valleys of the Jaguaribe river in the state of Ceará9,12,15,16. This uncontrolled spread led to 150,000 cases of malaria and 14,000 deaths in 8 months in both states9,17. The Northeast Malaria Service was created in the following year, exclusively to fight against the malaria African vector18. Larvicides incorporated with Paris green (i.e., copper acetoarsenite, an inorganic compound usually used as a rodenticide and an insecticide) were deployed, and all houses were fumed with pyrethrum9,19. In 1940, the malaria African vector was eradicated in Brazil13.
In view of the large number of cases reported in the 1940s, the National Malaria Service was created, but was quickly changed to the Malaria Eradication Campaign (CEM), which adopted the Global Malaria Eradication Program strategies of the World Health Organization (WHO)12,20,21. During this period, there was a significant and important impact on malaria transmission owing to the indoor application of dichlorodiphenyltrichloroethane (DDT) and the use of antimalarial drugs12,22,23.
The CEM was suspended in 1970 owing to the reduction of cases, criticism of the public health administrative model, and concerns regarding DDT use4. Malaria control activities are coordinated by the Superintendence of Public Health Campaigns, also responsible for the provision of antimalarial drugs for appropriate use and mass treatment, technical supervision, and use of outdoor ultra-low volume nebulization impregnated curtains and new insecticides3,4,21–23. At the end of 1998, the Pan American Health Organization released an analysis of the epidemiological situation of malaria in the Americas, in line with the initiative adopted by the WHO known as Roll Back Malaria24–25. In October 1999, the actions to reduce malaria in Brazil were conducted through the Plan to Intensify Malaria Control in the Legal Amazon (PIACM)24. However, despite the advances, several problems have not yet been solved, and the incidence of malaria remained high25. In 2003, the PIACM was replaced by the National Malaria Control Plan (NMCP)26 driven by objectives that aimed at reducing the morbidity, mortality, and severity of malaria along with stopping the transmission where possible.
MALARIA VECTORS IN BRAZIL: BIONOMICS AND BEHAVIORAL ASPECTS
The study of anopheline species in a region is important to direct vector control measures especially because the same species at the same site may change their habits over time, mainly as a result of environmental changes27–30. The main vectors in the Americas are widely distributed in diverse environments and present high variability in their behavioral patterns, even including intrapopulation31. In Brazil, 54 species of Anopheles mosquitoes are known, and the main vectors belong to two Anophelessubgenera: Nyssorhynchus and Kerteszia32–34. An. darlingi, An. aquasalis, and members of the An. albitarsis complex are the main transmitting species of malaria in the subgenus Nyssorhynchus31,33,34. Conversely, the subgenus Kerteszia is responsible for the transmission in the Atlantic Forest, notably An. cruzii and An. bellator35,36.
An. darlingi is considered the primary vector of malaria in Brazil29,32,37. It is collected in greater quantity in peridomiciles38. The largest period of hematophagic activity occurs during the first 3 hours of the escotophase39, varying from 18:00 to 21:00 or 17:00 to 20:00, depending on the type of locality, density of the Anopheles population, season of the year, distance between residences and forests, and presence of other hosts29,35,40,41. Large reservoirs of water where there are limited current and salinity are used as breeding grounds35,42. This species still bears uncertainties in relation to its biome and behavior, especially with regard to feeding habits, resting, and periodicity, which may be different according to locality32–35,37–42. Such differences in behavior can be explained by the high chromosomal polymorphism that allows the species to be able to explore different habitats, especially during the rainy season43–45.
An. aquasalis is found along coastal areas, in some localities that are approximately 100 and 200 km from the coast, and in soils rich in sodium chloride, as is the case in some areas of the northeastern backlands or in regions where tidal invasion occurs, such as Belém, Pará46–49. Galvão et al.47 pointed to the preferential zoophilic profile of An. aquasalis in Belém, Pará, where the climate is equatorial; conversely, An. aquasalis in the Northeast region, which has a semi-arid climate, presents anthropophilic habits49–52.
The albitarsis complex brings together the most common Anopheles mosquitoes widely distributed in Brazil, including An. oryzalimnetes, An. deaneorum, An. marajoara, and An. janconnae53–55. The cryptic species belonging to this complex cannot be distinguished morphologically in the adult phase; however, several methodologies were used for identification, including allozymes and DNA-based techniques53–59. The members of the albitarsis complex have large distributions, as well as high behavioral variabilities60. Their preferred breeding sites are clean freshwater reservoirs, preferably in sunny or shaded fields and pastures. In most of the Brazilian territory, they present zoophilic and exophilic habits60.
The anophelines An. cruzii and An. bellator breed in bromeliads in the Atlantic Forest and have acrodendrophic habits, a behavioral characteristic of mosquitoes of the subgenus Kerteszia, especially An. cruzii; this refers to the preference of these vectors in practicing hematophagy in the crown of trees, occasionally descending to the ground, which results in the accomplishment of repasts in the two heights of the forest42. An. cruzii is restricted to the Brazilian coast, where it is a transmitter of the Plasmodium vivax, P. simium, and P. brasilianum, causing human and simian malaria61–69. It is found in peridomiciliary environments, with its 24-hour activity peaking in the crepuscular periods of the day65,67,68. An. bellator is found only on the coast and presents eclectic habits regarding hosts. It has preference in breeding in bromeliads exposed to the sun70.
VECTOR CONTROL IN BRAZIL
Vector control is an essential component of malaria prevention71. In Brazil, it was initially performed through early management of mosquitoes with the use of Paris green and petroleum derivatives5,7,9. With the discovery of DDT, the focus of malaria control strategies shifted to managing the adult mosquito population. DDT spraying was officially conducted throughout the Amazon in 196012. Indoor spraying of DDT was banned in Brazil in 1999 because of its ecotoxicological risks, and currently, several classes of insecticides have been used, with special emphasis on pyrethroids, etofenprox PM 20% and lambdacyalothrin CE 5%72,73. Further, different methods for vector control have been used in the field (Figure 1).
INTERVENTIONS BASED ON IRS
Aimed at adult mosquitoes, IRS consists of spraying the interior walls of houses with insecticides71,74. Once applied, the insecticide will form a film of small crystals on the surface, killing the vector when it rests on the wall before or after a meal of blood75. Some of the insecticides used in IRS are also capable of repelling mosquitoes, reducing the number of vectors entering the households. It has been the most widely used method in malaria vector control75, with some official guidelines available75–78.
Some researchers have evaluated the effectiveness of different IRS insecticides used in Brazil. Roberts and Alecrim79 investigated the behavioral alterations in female An. darlingi mosquitoes after DDT spraying, observing that they stopped entering and leaving houses, with a reduction in the bite rate. However, IRS did not interfere with the persistence of malaria in the study area, probably owing to the sprayed houses presenting incomplete walls. In their field trial, Charlwood et al.80 compared the effects of lambdacyalothrin (ICON) and DDT when used as residual sprays on the internal surfaces of houses. ICON killed more mosquitoes than did DDT. From the observed efficacy, prompt acceptance by the local population, and cost-effectiveness of ICON, the authors have suggested its use in antimalaria campaigns. Santos et al.81 evaluated the residual effect of pyrethroids on Anopheles mortality. The insecticides used were a suspension of deltamethrin, pyrethroids, lambda-cyhalothrin, and etofenprox in wettable powder, which were sprayed onto the surface of local dwellings. The authors observed that the insecticides applied to wood and uneven surfaces were more stable and lasted longer. Based on the findings of the study by Santos et al.81 the NMCP changed the insecticide from alpha-cypermethrin to etofenprox in 2013.
Etofenprox PM 20% is the insecticide used by the Ministry of Health for residual spraying in houses for vector control of malaria. This product has a residual effect for 4 months81; therefore, three annual application cycles are required. This insecticide is applied by municipalities quarterly by filling out a standardized worksheet with the following information: (i) number of properties to be worked on in each cycle and (ii) number of malaria cases in the same period of the previous year and updated inventory of the insecticide in the municipality (Figure 2). For the Indigenous Special Sanitary Districts (DSEIs), etofenprox PM 20% application is conducted by sending a request with the abovementioned data directly to the Ministry of Health (Figure 3).
Although the work performed by different authors in Amazonian communities showed the role of IRS, it is still necessary to evaluate the effectiveness and costs of this action more specifically, as it is mainly related to the reduction of the morbidity of malaria in the Amazon.
Rapid coverage of the population at risk through free and/or subsidized distribution of ITNs has been recommended by the WHO as a primary intervention for malaria control based on evidence of efficacy and effectiveness that this intervention has demonstrated in Africa, Southeast Asia, and South America82. Currently, there are long-lasting insecticidal nets (LLINs) that have a shelf life of approximately 2-3 years in the field or should be effective for 20 laboratory washes, with pyrethroid insecticides incorporated in the fabric83,84.
ITNs emerged in the 1990s as one of the great hopeful methods of controlling malaria worldwide. In Brazil, the Ministry of Health started to distribute ITNs freely in malaria-endemic areas in 200785. Between 2012 and 2014, there was an increase in the number of protected individuals with this strategy; however, there were discontinuity and subsequent reduction in the following years. LLINs impregnated with deltamethrin have been used in the Amazon38; however, the results have been contradictory, and there is limited knowledge on the effectiveness of ITNs in affecting the morbidity and mortality of malaria. The biting behavior of An. darlingi mosquitoes can be the main reason why ITBN-based malaria control programs may fail in this region38,82,86–89.
In Brazil, the first work with ITNs was performed by Xavier and Lima86and Cavalcante et al.87 who demonstrated the efficiency of DDT and deltamethrin and the effective repellent effect for up to 120 days, persisting even longer in locations not exposed to sunlight. Santos et al.40 showed that ITNs used in Costa Marques, Rondônia did not change the risk of Plasmodium infection and did not reduce the cases of malaria and the average parasitemia associated with infection as observed in other continents. Probably, the protection failure of nets may have been attributed to bites occurring before entering and after leaving the mosquito net, to the more frequent exits during the night, and to the exophilic and endophilic behaviors of the main vector species in the region. These authors also showed that ITNs significantly decreased the number of Anopheles mosquitoes captured; however, impregnated and non-impregnated ITNs showed similar actions on the peridomiciliar density of mosquitoes. Still in Brazil, Galardo and Galardo88 conducted a study in Mazagão, Amapá, evaluating the residual effect of ITNs impregnated with alpha-cypermethrin and observing an 80% reduction in malaria cases in the municipality. In 2012, approximately 150,000 LLINs were installed in nine municipalities in the state of Rondônia; Vieira et al.89evaluated the use of LLINs in nine cities and compared the outcomes with those in cities where LLINs were not used. However, no significant differences were observed in the annual parasite incidence 1 year after LLIN installation.
OTHER VECTOR CONTROL MEASURES
Space and aerial spraying
A spatial spray (fog) is a liquid insecticide dispersed into the air in the form of hundreds of millions of tiny droplets less than 50 µm in diameter90. Currently, neither space spraying nor aerial spraying has a WHO policy recommendation for use in malaria vector control91. Fogging might be justified for control of certain exophilic and exophagic vectors and during malaria epidemics, especially in camps for internally displaced individuals, where infective mosquitoes must be eliminated rapidly26,92. This will be important in vector control only in epidemiological emergencies and should never be used as a routine activity92. In Brazil, thermal fogging was selectively and exceptionally used in specific areas depending on entomological and epidemiological conditions, including areas of mining or those with lack of vegetation, as was the case in the Belo Monte site93. Measures, such as thermal fogging, are widely used in the Amazon for malaria control; however, they may be only slightly effective if not performed according to the mosquitoes’ blood feeding activity94. Further, there is no evidence of the impact of nebulization or spatial spraying of insecticides on malaria transmission.
Lambdacyalothrin CE 5% is the insecticide currently used in Brazil for thermonebulization in malaria control, recommended only in epidemic situations; its application is not a routine activity of the malaria program. The application follows the same flow for municipalities and the Departamento de Saúde Especial Indígenas (DSEIs), but without the use of programming worksheets (Figure 2).
Larval source management (LSM)
LSM targets the immature, aquatic stages of mosquitos (i.e., larvae and pupae), thereby reducing the abundance of adult vectors95. The use of bacterial entomopathogens, such as Bacillus sphaericus and B. thuringiensis israelensis (Bti), is an alternative to conventional control measures against Anopheleslarvae96,97. Bti is a bacterium that produces proteins, such as δ-endotoxins, which are toxic to larvae of several insects98,99. Rodrigues et al.100,101 analyzed the larvicidal activity of B. sphaericus against larvae of anophelines in Amazonian conditions. They showed that the third larval instar of An. nuneztovari and the second and third larval instars of An. darlingi proved to be the least susceptible, while An. braziliensiswas the most susceptible.
Galardo et al.102 evaluated an intervention for malaria vector control using VectoLex(r) CG (granular formulation of B. sphaericus 2362 strain) at a mining site in Calçoene, Amapá. The VectoLex(r) reduced immature An. darlingi infestation levels during the entire study period and reduced adult mosquito populations during the rainy season.
Additionally, there are insect growth regulators, which prevent emergence of adults from the pupal stage. The most common compounds are diflubenzuron, methoprene, novaluron, and pyriproxyfen95.
Insecticide resistance is the ability of insects to survive exposure to a standard dose of insecticide, owing to physiological or behavioral adaptation103. The molecular basis of insecticide resistance has been justified by the existence of mutations in insecticide target site genes and alterations in related metabolic pathways, including primarily the detoxification activity104. Behavioral resistance results from sub-lethal exposure to the active ingredient of insecticides and involves behavioral changes, resulting in avoidance and reduced contact with lethal doses of an insecticide105. Although the mechanisms of resistance to insecticides are known, the impact of resistance on the ability of malaria control interventions to reduce disease transmission is poorly understood106.
Through the Global Plan for Insecticide Resistance Management in Malaria Vectors created by the WHO107, the basis of any national vector control strategy was constructed, which includes a system based on epidemiological and entomological monitoring and monitoring of resistance to insecticides used, based on bioassays using WHO paper bioassays104 or CDC bottle bioassays108. Ecological, epidemiological, and susceptibility information will help determine the proper use of insecticides to mitigate or delay the development of resistance.
Galardo et al.109 evaluated the susceptibility of anophelines from Amapá to pyrethroids used by the NMCP, and no resistance was recorded for An. darlingi; however, An. marajoara requires attention. Silva et al.110evaluated the susceptibility profile of pyrethroid insecticides on An. darlingi and An. marajoara larvae. In this study, loss of susceptibility was observed in the populations of Manaus and Iranduba, possibly owing to the selection effect of the insecticides on the specific resistance alleles. Resistant mosquito populations may also appear owing to the long-term use of a single insecticide for malaria control vectors.
OFFICIAL RECOMMENDATIONS FROM THE BRAZILIAN MALARIA CONTROL PROGRAM
Two guidelines for malaria control are available from the Ministry of Health for professionals77 and local management26. Through the Guide to Local Management of Malaria Control26, the Ministry of Health establishes important recommendations on the methodologies for controlling anopheline malaria vectors in the country. According to this guide, vector control should follow the principles of selective and integrated control, with community participation and adjusted to the eco-epidemiological situations of each municipality. For this, the central axis of the vector control is the timely use of epidemiological information and the consolidation of a work routine in entomology with robust data on the parameters that must be monitored to support decision-making26.
A careful and systematic analysis of the effect of control actions on malaria behavior depends essentially on the adequate completion and use of the information from the Malaria Epidemiological Surveillance System (Sivep-Malária)26. After identification of the priority areas, previously collected and updated local characterization information will help select the localities needing IRS and/or use of LLINs and those where control measures for breeding sites are necessary. In addition, adequate training and good maintenance of equipment avoid risks to human and environmental health, as well as economic losses26.
IDENTIFYING RESEARCH PRIORITIES IN VECTOR CONTROL
In the national meeting on malaria research that took place in Recife, Pernambuco, in 2018, some gaps were identified for malaria vector control in Brazil. Considering such, some of the needs and priorities for future research and interventions include as follows:
Update of the cartography of malaria vectors in Brazil, adding molecular techniques for the correct identification of species and complexes of species;
Evaluation of vector competence of anopheline species in Brazil;
- Strengthening of local entomology teams to perform vector control measures and interpret results;
- Evaluation of vector control measures, especially the use of ITNs and LLINs, through community trials, estimating their effectiveness, cost-benefit, and population acceptance;
- Establishment of colonies of malaria-transmitting vectors in Brazil, with emphasis on An. darlingi, to understand parasite-vector interactions better;
- Study of new vector control strategies with impact on non-endophilic vectors;
- Estimation of the impact of insecticide resistance in different geographical areas, considering the insecticides indicated by the NMCP;
- Identification of the relative contribution of natural and artificial breeding sites in different epidemiological contexts for transmission
Vector control is an essential component of malaria prevention. In summary, incorporating vector control interventions, such as use of ITNs and IRS, is suggested for malaria elimination. Further confirmation from interventional studies is crucial to provide additional evidence for updating the malaria elimination policies in the territory. Vector control surveys are needed to address responses to changes in the NMCP guidelines, especially in the context of changes to eliminate malaria transmission in Brazil.