Treatment of Marburg and Ebola hemorrhagic fevers: A strategy for testing new drugs and vaccines under outbreak conditions

Abstract

The filoviruses, Marburg and Ebola, have the dubious distinction of being associated with some of the highest case-fatality rates of any known infectious disease—approaching 90% in many outbreaks. In recent years, laboratory research on the filoviruses has produced treatments and vaccines that are effective in laboratory animals and that could potentially drastically reduce case-fatality rates and curtail outbreaks in humans. However, there are significant challenges in clinical testing of these products and eventual delivery to populations in need. Most cases of filovirus infection are recognized only in the setting of large outbreaks, often in the most remote and resource-poor areas of sub-Saharan Africa, with little infrastructure and few personnel experienced in clinical research. Significant political, legal, and socio-cultural barriers also exist. Here, we review the present research priorities and environment for field study of the filovirus hemorrhagic fevers and outline a strategy for future prospective clinical research on treatment and vaccine prevention.

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.