Treatment of Marburg and Ebola hemorrhagic fevers: A strategy for testing new drugs and vaccines under outbreak conditions
Introduction
The filoviruses are nonsegmented, single-stranded negative-sense RNA viruses with an unusual filamentous morphology. The family Filoviridae is divided into two genera, Ebolavirus and Marburgvirus. Four species of ebolavirus (Zaire, Sudan, Ivory Coast and Reston) and one of marburgvirus (Lake Victoria marburgvirus) are recognized (Table 1). Filoviruses circulate in sub-Saharan Africa where they occasionally cause large outbreaks of severe hemorrhagic fever (Fig. 1) (Bausch, 2007a). The natural reservoir of the filoviruses remains unknown, although bats are suspected (Leroy et al., 2005, Swanepoel et al., 2007, Towner et al., 2007). Transmission between humans results from direct contact with infected blood and bodily fluids (Dowell et al., 1999, Bausch et al., 2007b). No specific antiviral therapies or vaccine are yet available. The primary control strategy relies on thorough case identification and contact tracing, with immediate isolation of suspected cases in specialized isolation wards (CDC/WHO, 1998, Bausch, 2007b).
Increasing frequency of natural transmission of the filoviruses in sub-Saharan Africa, as well as concerns about bioterrorism and imported cases, have heightened their importance to public health over the past few decades. These concerns have fostered intense laboratory-based research efforts in industrialized countries on the pathogenesis, treatment, and vaccine prevention for filovirus hemorrhagic fever (FHF) that hold the potential to reduce case-fatality rates and drastically curtail outbreaks (Schuler, 2005). Several candidate therapies have shown efficacy in nonhuman primates if initiated soon after virus challenge, and a number of vaccines have been developed that protect these animals against otherwise uniformly lethal infection.
The research advances on treatments and vaccines for FHF may soon render products ready for clinical testing. However, while the basic science stages of research takes place largely in the controlled environment of high-containment laboratories, if clinical research on FHF is to be carried out it must occur in endemic areas in sub-Saharan Africa, most likely under outbreak conditions in areas with rudimentary medical infrastructures. In fact, any plan to conduct prospective clinical research on FHF must deal with a staggering array of scientific, logistical, political, social, financial, legal, and ethical challenges. Here, we review the progress made to date in understanding the pathogenesis, clinical presentation, treatment, and vaccine prevention of FHF, then describe the settings in sub-Saharan Africa where field research on FHF must take place, and finally outline a strategy for prospective clinical research on treatment and vaccine prevention in this challenging environment.
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Research progress
A decade of work by teams at the Centers for Disease Control and Prevention (CDC), the US Army Medical Research Institute for Infectious Diseases, the Public Health Agency of Canada and other laboratories has led to major progress in understanding the pathogenesis of the FHFs and developing experimental therapies and vaccines. Studies have been based on models of infection in mice, guinea pigs, and nonhuman primates, supplemented by a limited amount of clinical data obtained from humans during
Filovirus outbreaks—controlled chaos
Except for outbreaks related to the inadvertent importation of infected monkeys to Europe, cases of FHF in humans have been exclusively noted in sub-Saharan Africa (Table 1 and Fig. 1). Although seroprevalence data suggest that some degree of endemic transmission probably exists beneath the threshold of detection, especially for ebolaviruses (Monath, 1999, Bausch et al., 2003), filovirus transmission is generally recognized only in outbreak form (Bausch, 2007a). The largest outbreaks (300–400
A strategy for bringing research products to field testing
The recent success in developing therapies and vaccines that protect laboratory primates against the filoviruses suggests that similar approaches may be effective in humans. However, the typical setting of a filovirus outbreak in Central Africa, the only place where human efficacy trials might be possible, presents an extreme contrast to the highly controlled, resource-rich environment of high-containment laboratories in industrialized countries. Although human efficacy trials might be avoided
Conclusions
Filoviruses continue to plague populations in Central Africa, with increasing frequency and size of outbreaks in the last decade. Meanwhile, industrialized countries have conducted intensive laboratory-based research that is starting to produce promising therapies and vaccines, bringing the issue of clinical trials to the forefront. A successful clinical research program for filoviruses will likely only be established through concerted advanced planning and the cooperation of a broad array of
Acknowledgements
The authors thank Corrie West and Jessie Dyer for assistance preparing the manuscript.
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