Invited submission
Filovirus emergence and vaccine development: A perspective for health care practitioners in travel medicine

https://doi.org/10.1016/j.tmaid.2010.05.003Get rights and content

Summary

Recent case reports of viral hemorrhagic fever in Europe and the United States have raised concerns about the possibility for increased importation of filoviruses to non-endemic areas. This emerging threat is concerning because of the increase in global air travel and the rise of tourism in central and eastern Africa and the greater dispersion of military troops to areas of infectious disease outbreaks. Marburg viruses (MARV) and Ebola viruses (EBOV) have been associated with outbreaks of severe hemorrhagic fever involving high mortality (25–90% case fatality rates). First recognized in 1967 and 1976 respectively, subtypes of MARV and EBOV are the only known viruses of the Filoviridae family, and are among the world’s most virulent pathogens. This article focuses on information relevant for health care practitioners in travel medicine to include, the epidemiology and clinical features of filovirus infection and efforts toward development of a filovirus vaccine.

Introduction

MARV and EBOV belong to the Filoviridae family of single-stranded negative-sense RNA viruses. Filoviridae derive their name from the Latin word “filum” based on their filamentous structure. Since discovery in 1967 and 1976 respectively, MARV and EBOV have caused several outbreaks concentrated in sub-Saharan Africa but some sporadic cases have occurred elsewhere. These have been mostly related to travel, nosocomial infections and occupational contact with infected animals from the endemic regions.1, 2

MARV and EBOV are considered re-emerging and highly infectious pathogens. Human outbreaks have been sporadic, involve high case-fatality, and are socially and economically disruptive.3 The dramatic clinical manifestation of both MARV and EBOV, with severe hemorrhaging in most cases, has also contributed to the high publicity and fear around outbreaks and imported cases.4 Due to their highly infectious nature and potential for use in biological weapons, MARV and EBOV are classified as Category A bioterrorism agents according to the US Centers for Disease Control and Prevention (CDC).

The genus EBOV is divided into five different species. These five species are named based on the location of recognition and include Zaire, Sudan, Ivory Coast, Bundibugyo and Reston viruses (Fig. 1). The Zaire species was first recognized in 1976 in a large outbreak in Yambuku with over 300 cases and a fatality rate of 88%. Since then it has been the cause of several outbreaks with high mortality rates ranging from 50 to 80%. The Sudan species has been the cause of four epidemics to date; three outbreaks in Sudan and one in Uganda. The Ivory Coast species was first recognized when it was identified as a causative agent of illness in a scientist conducting an autopsy on an infected chimpanzee. The Bundibugyo species emerged in Uganda in 2007 causing an outbreak of over a hundred cases with a mortality rate of over 30%. Lastly, the Reston species was described in 1989 when it caused a lethal outbreak in macaques imported to the US from the Philippines. This species caused three more outbreaks in the USA and Europe in non-human primate (NHP) facilities. The laboratory workers taking care of the infected animals developed antibodies to this virus but did not develop any clinical illness.5, 6 In contrast to the Ebola virus, all strains of the MARV are considered members of a single species, the Lake Victoria Marburg virus. However the species encompass different strains and these strains vary in their pathogenicity in humans. This observation is based on different mortality rates among several past outbreaks caused by MARV.1

The filoviruses are zoonotic viruses that are believed to be transmitted to humans from animals. In a given outbreak, attempts have been made to trace the virus from the index cases. Despite aggressive attempts, the natural reservoir remains unknown. NHPs were initially proposed as maintenance hosts for filoviruses since the initial cases of the disease were recognized in imported infected monkeys. This hypothesis does not seem plausible as susceptibility of non-human primates to fatal infection with these viruses would make them poor host reservoirs. In fact, EBOV has afflicted large populations of NHPs and this has led to a significant decline in chimpanzee and gorilla populations in Gabon and Congo.7, 8 While the source of filoviruses in nature has not been definitively identified, increasing evidence suggests that bats may serve as reservoirs.

Human outbreaks that occurred between 2001 and 2005 in Gabon and Democratic Republic of Congo were linked to concurrent gorilla and chimpanzee outbreaks. Field collections in the region revealed Ebola specific immunoglobulin in three different bat species.9 In September 2007, mine workers in Kitaka Cave in Uganda were diagnosed with Marburg fever. The likely source of this infection in the mine workers was thought to be due to exposure to Egyptian fruit bats. This was based on detection of MARV RNA and virus specific antibody in bat sera.10 Further evidence to support the hypothesis that bats may in fact be harboring these deadly viruses comes from recent imported cases of Marburg infection. Both individuals contracted the infection after visiting the Python Cave in the Queen Elizabeth National Park in Uganda miles away from the Kitaka mines where the 2007 MARV outbreak had occurred.11

Section snippets

Clinical manifestations of Marburg and Ebola hemorrhagic fever

MARV and EBOV infections are similar in their clinical presentation, manifesting as hemorrhagic fever. Ebola hemorrhagic fever is a severe and often fatal disease affecting both humans and non-human primates. Most of the knowledge and clinical information comes from persons infected by the Sudan and Zaire species, which are the most virulent strains. The Bundibugyo species was observed to have a slightly lower mortality rate of approximately 30%. In contrast, the Reston species has not caused

Transmission

Presumably, most index cases occur due to contact with an infected animal. Transmission of the virus from person to person occurs as a result of direct contact with virus containing body fluids. Infectious body fluids include blood, vomitus, urine, feces, sweat, breast milk, saliva and respiratory secretions. Epidemiological studies have demonstrated that family members are at risk of infection if they have had contact with infected body fluids or have helped to prepare the corpse of an

Pathogenesis and laboratory abnormalities

At the site of entry into the body, MARV and EBOV infect macrophages and other cells of the phagocytic system.12 Dendritic cells and macrophages are the primary cells for viral replication. Macrophages are highly susceptible to infection and generate large numbers of viral particles and hence serve as vehicles for delivery of the virus to a variety of organs including the liver, endothelium, spleen, lymph nodes, kidney, adrenal gland, and pancreas.14 Marked leukopenia with a left shift and

Diagnostic tests

Diagnostic tests available for MARV and EBOV infections are research based assays and include virus isolation, detection of viral antigens in blood and body fluids using an enzyme linked immunosorbent assay (ELISA) and recognition of specific RNA sequences by reverse transcription polymerase chain reaction (RT-PCR).21 Confirmation of diagnosis can be done by isolating the causative agent in cell culture and visualizing viral particles using electron microscopy. These tests can only be performed

Treatment

There is currently no specific antiviral therapy available for Ebola or Marburg hemorrhagic fever and treatment is purely supportive. The clinical manifestations seen in filovirus hemorrhagic fever occur as a result of the host response to the viral infection and supportive care should be focused at maintenance of effective circulatory volume, blood pressure and perfusion. Fluid administration for intravascular volume resuscitation and transfusions for correction of coagulopathy and hemorrhage

Discovery, outbreak history, and imported cases

In August 1967, simultaneous accounts of malaise, headache, fever, nausea, vomiting, and diarrhea along with other unusual symptoms were reported in Marburg and Frankfurt, Germany. Preliminary diagnoses were dysentery and typhoid fever but these were ruled out.31 Microbiological and epidemiological investigation later showed that thirty-two individuals, in both Germany and Yugoslavia, had been exposed to the newly identified MARV after contact with the blood, organs and cell cultures of

Imported case 1

On July 10, 2008, the Dutch National Institute for Public Health and the Environment released a statement announcing confirmation of MARV infection in a 41-year old woman who had recently returned from travel in Uganda.38

Case summary38–40

A 41-year old Dutch female spent June 5 through June 28, 2008 touring Uganda, including visits to an empty cave on June 16 in Fort Portal and the attraction known as the Python Cave in the Maramagambo Forest, Queen Elizabeth Park on June 19. The Python cave is famous for the presence of a large number of pythons and bats and there had been reports of bats coming into contact with cave visitors.39

On July 5th, after 3 days of chills and fever, she was referred to Elkerliek Hospital by her primary

Imported case 2

On January 22, 2009, the US Centers for Disease Control and Prevention retrospectively diagnosed a case of Marburg virus infection in a US tourist who had been severely ill after vacationing in Uganda in December of 2007.41

Case summary6,11,41,42

A 44-year old American woman spent December 17 through December 31, 2007 touring Uganda, including a visit to the Python Cave in the Maramagambo Forest, Queen Elizabeth Park.

On January 4, 2008, four days after returning home to Denver from her vacation to Uganda, the female traveler experienced severe headache, chills, nausea, vomiting, and diarrhea. She also noted a loss of appetite and vaginal bleeding out of her normal cycle. Between January 6th and 7th, she consulted a physician, began

Vaccine research

Beyond the morbidity and mortality experienced by individuals, regions affected by filovirus outbreaks suffer a negative economic impact. Imported cases of Marburg infection also highlight the risk of spread that can occur as a result of travel.

There is no approved vaccine for use to prevent EBOV or MARV infection and no effective therapy available against filoviruses. Hence, development of a safe and effective vaccine remains a goal of researchers and public health officials.

Due to theoretical

Conclusion

EBOV and MARV are important viral pathogens and have the ability to cause devastating human disease, as seen in regional outbreaks and imported cases. A safe, effective and immunogenic vaccine would be a significant step forward in addressing the public health threat that filoviruses continue to pose. Preventive vaccination could potentially be used to provide protection for first responders, travelers, medical personnel, those at risk due to occupational exposures, military troops, as well as

Conflict of Interest

None.

Acknowledgements

The authors thank Dr. Barney S. Graham, Dr. Ed Tramont and Michelle Barnes for their review of the manuscript.

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