Problems and Challenges for Disease Control
Dengue
Potential for Vaccine Development
The occurrence of DHF in children and adults with previous dengue antibodies, acquired passively or actively, has been the most important challenge for the development of a dengue vaccine. Lack of a suitable animal model, insufficient knowledge of disease pathogenesis, and limited research funding have also had a negative influence. Researchers generally agree that a dengue vaccine must confer long-lasting protection against the four dengue serotypes. Currently, they are following different strategies in the development of several vaccine candidates. Some vaccines are currently undergoing human clinical trials—for example, live attenuated dengue and yellow fever chimeric vaccines. The conventional live attenuated vaccines are entering phase 3 trials, while the chimeric vaccines are presently in phase 1 and phase 2 trials. Others are in the preclinical phase of development. To accelerate the development of a dengue vaccine, a new initiative—the pediatric dengue vaccine initiative—has been launched, with the major objective of mobilizing resources to accelerate the development of a safe and effective pediatric dengue vaccine (Almond and others 2002; Halstead and Deen 2002; Pang 2003).
Vector Control
Without a vaccine, vector control remains the only available strategy against dengue. Selective, integrated vector control with community and intersectoral participation, active disease surveillance based on a strong health information system, emergency preparedness, capacity building and training, and vector control research constitute the major elements of WHO's global strategy for dengue prevention and control. Since the eradication era, few examples of successful dengue prevention and control on a national scale are available. Exceptions include Cuba and Singapore, both island states. Cuba, with approximately 11 million inhabitants, has been able to interrupt dengue transmission. Despite being in an endemic area, the country has maintained low vector densities and has successfully controlled epidemics in recent years (Arias 2002). Critical factors contributing to this achievement are the strong dengue surveillance system, which integrates environmental, entomological, epidemiological, clinical, and virological surveillance in conjunction with the public health infrastructure, and a strong vector control program, along with good intersectoral coordination, active community involvement, and strong political commitment.
A limited array of tools is available for vector control interventions, any one of which can control at least part of the vector population or provide personal protection. However, approaches are converging, at least at the policy level, toward application of vector control tools through social or community mobilization. Consensus is growing that community-based approaches are desirable and necessary, and many believe that only through such approaches can a degree of sustainability be accomplished in relation to dengue vector control. Even though few such interventions have expanded beyond the pilot stage, the decentralization of budgetary and operational responsibilities for program delivery appears to offer opportunities for strengthening and expanding this integrated vector management approach.
Increasing levels of resistance of Ae. aegypti to temephos imply shorter intervals between treatments. This situation is already a reality in some countries, including Brazil and several Caribbean islands (Carvalho and da Silva 1999; Rawlins 1998). Resistance of adult mosquitoes to malathion and to pyrethroids has been reported in the Americas and in Asia (WHO 1992) and is likely to reduce the efficacy of space spraying. Given the peridomestic ecology of Ae. aegypti in most regions and the widespread use of pyrethroids for public health purposes and in household insecticide products, the rate of development of pyrethroid resistance is likely to accelerate. At the same time, few new insecticide products are becoming available in the public health market because of the costs involved in development and registration compared with the returns on investment from the relatively small commercial market. The high cost of re-registration of existing products is also contributing to the withdrawal of some insecticides from the market.
New Risk Factors
Environmental changes, particularly those related to climate, directly affect the incidence and prevalence of vectorborne diseases. However, social factors, such as lifestyles and population density, particularly in the case of dengue, are also important. Using an empirical model of the effect of population and climate change on the global distribution of dengue fever, Hales and others (2002) conclude that predicted changes in humidity will increase the areas with a climate suitable for dengue transmission.
The world is also becoming increasingly urbanized: during 2000-25, Asia's urban population is expected to double, and that of Latin America and the Caribbean is expected to increase by almost 50 percent. The resulting high human population densities, coupled with lifestyles that increasingly contribute to the proliferation of larval habitats and infrastructural deficiencies in relation to water supply and sanitation, are such that effective delivery of vector control on the scale needed is beyond the reach of many governments. The increasing global trend in international travel also facilitates the dissemination of virus serotypes and strains between vulnerable populations.
Genetic variability is another element to be considered. The genetic diversity of the viruses is increasing, with some genotypes associated with severe disease (Cologna and Rico-Hesse 2003; Leitmeyer and others 1999; Rico-Hesse and others 1997). Recombination has been demonstrated in all four serotypes, but the implications in terms of pathogenesis are unknown. In addition to recombination, mutations, gene flow, and other factors could further influence the genetic diversity and selection of virulent strains (Holmes and Burch 2000). At the same time, in addition to initial observations of the higher risk of DHF in Caucasian than in those of African descent, a few reports associate some human leukocyte antigen alleles with disease severity (Bravo, Guzman, and Kouri 1987; LaFleur and others 2002; Loke and others 2001; Paradoa, Trujillo, and Basanta 1987; Stephens and others 2002). The sequence of infecting viruses and, more recently, the longer interval between primary and secondary infection as a risk factor for DHF, add a new perspective to the problem (Guzman and others 2002; Nisalak and others 2003).
Leishmaniasis
Because the primary control strategy against leishmaniasis is based on case finding and treatment, the priority for control is developing and implementing improved diagnostic methods and better treatments that are more amenable to field use. A parallel requirement is for the development of more cost-effective drug delivery systems, especially ones that take advantage of new oral drugs, such as miltefosine, and the planned registration and local production of aminosidine in India.
Improved Diagnostics and Treatment
Even though the new serological tests, such as the dipstick, lyophilized direct agglutination test kit, and latex agglutination urine test, represent major improvements, they are not yet widely used in endemic countries. Moreover, they are indirect tests that cannot provide direct parasitological confirmation of infection or of cure immediately following treatment. Current parasitological tests tend to be highly invasive and can be costly to perform; therefore, simple molecular-based tests would be an advantage.
For leishmaniasis treatment, development of the oral VL drug, miltefosine, represents a substantial improvement, but it remains expensive and with a long treatment regimen and cannot be administered to pregnant women because of the risk of teratogenicity. Further clinical evaluation is required to establish the possibility of shorter treatment regimes and the potential of combination therapy to inhibit the development and spread of drug resistance. Another oral drug, sitamaquine, is currently under development and will require similar clinical and implementation studies. Clinical trials of aminosidine (paromomycin) are proceeding, and use of this drug against VL may become widespread. An improved understanding of disease pathogenesis would be helpful in refining the criteria for cure and in improving patients' prognosis.
Vaccine Development
The leishmaniases offer substantial opportunities for vaccine development, and a crude vaccine against CL has been widely used in parts of the Middle East. Trials of a second-generation vaccine that includes three Leishmania antigens are currently in progress.
Vector Control
Control of domestic and peridomestic sand-fly vectors will probably continue as an additional benefit accruing to programs against other insect vectors using indoor residual spraying or insecticide-treated bednets. However, in areas where dogs are among the main reservoir hosts, increased use of insecticide-treated dog collars would merit further appraisal. Such collars not only would reduce the likelihood of new infections in dogs, but also could reduce the risk of transmission from dogs to humans.
African Trypanosomiasis
Improved Diagnostics
Serological diagnosis is reliable for verifying infection; however, most district hospitals or peripheral health units have neither the facilities nor the necessary expertise to perform and read serological tests. In the past, serological diagnosis, based on indirect fluorescent antibody tests and ELISA, was restricted to central-level facilities or specialized mobile teams. The card agglutination trypanosomiasis test has substantially simplified the use of serology but requires specifically equipped health units with a cold chain. Parasitological diagnosis, such as the miniature anion exchange centrifugation test, is more expensive and complicated to use in field surveys despite the development of a simplified sterile kit version. Molecular diagnostics are not yet developed to a level appropriate for widespread field use.
Treatment
Despite the availability of drugs free of charge from WHO, treatment is hampered by the length of hospitalization required and by the toxicity of currently available drugs. In addition, inability to use the same drug in the early and late stages of the disease complicates the treatment protocol. The existing late-stage drug, melarsoprol, is unsafe, its secondary reactions are numerous, and the occurrence of a lethal encephalopathic syndrome in 5 to 10 percent of treated cases means that patients on melarsoprol must be hospitalized. A new oral drug for the early stage, soon to be registered, must be introduced in the field, which will take several years.
Drug resistance is well established in animal trypanosomes. For T. congolense, T. vivax, and T. evansi, resistance to all available drugs has been reported, along with trypanosome populations with multiple drug resistance (Geerts and Holmes 1998). Much less information is available on human pathogenic trypanosomes. The resurgence of human African trypanosomiasis in recent years has been accompanied by increasing reports of treatment failure using melarsoprol. As early as 1960, T.b. rhodesiense patients in Uganda were reported to have relapsed after two or more courses of melarsoprol, and in 1977, a 40 percent melarsoprol relapse rate was reported in the DRC.
Relapses after treatment with early-stage drugs remain rare. Whether relapses after melarsoprol treatment reflect parasite drug resistance or host factors is unknown. Furthermore, even though increasing rates of melarsoprol failure have been observed in several countries, the magnitude and geographic distribution of the problem have not been determined. Analyses of existing data are complicated by the lack of a standard treatment regimen and the range of clinical and laboratory criteria used to define a relapse.
Vector Control
Even though available techniques to control tsetse flies can be highly effective (Maudlin, Holmes, and Miles 2004), all are constrained by the difficulties of applying them on a large enough scale for long enough to achieve sustainable results. Insecticide spraying is efficient but is difficult to sustain because of logistical constraints and high costs. Targets and traps are effective, but their deployment is difficult to sustain for long periods, and implementation through community participation requires constant motivation and supervision to remain effective. To address these problems, the African Union has launched the Pan African Initiative (PATTEC), which focuses on identifying regions where elimination of the tsetse fly may be feasible using currently available techniques. This initiative is designed as part of a poverty reduction strategy that aims at eliminating the problem of tsetseborne animal trypanosomiasis, but in several areas it will also reduce the risk of human infections.
