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Review
. 2015 Jun;65(3):241-59.

A Comparison of the Pathogenesis of Marburg Virus Disease in Humans and Nonhuman Primates and Evaluation of the Suitability of These Animal Models for Predicting Clinical Efficacy under the 'Animal Rule'

Elizabeth R Glaze  1 , Michael J Roy  2 , Lonnie W Dalrymple  2 , Lynda L Lanning  3
Affiliations
Review

A Comparison of the Pathogenesis of Marburg Virus Disease in Humans and Nonhuman Primates and Evaluation of the Suitability of These Animal Models for Predicting Clinical Efficacy under the 'Animal Rule'

Elizabeth R Glaze et al. Comp Med. 2015 Jun.

Abstract

Marburg virus outbreaks are sporadic, infrequent, brief, and relatively small in terms of numbers of subjects affected. In addition, outbreaks most likely will occur in remote regions where clinical trials are not feasible; therefore, definitive, well-controlled human efficacy studies to test the effectiveness of a drug or biologic product are not feasible. Healthy human volunteers cannot ethically be deliberately exposed to a lethal agent such as Marburg virus in order to test the efficacy of a therapy or preventive prior to licensure. When human efficacy studies are neither ethical nor feasible, the US Food and Drug Administration may grant marketing approval of a drug or biologic product under the 'Animal Rule,' through which demonstration of the efficacy of a product can be 'based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is reasonably likely to produce clinical benefit in humans.' This process requires that the pathogenic determinants of the disease in the animal model are similar to those that have been identified in humans. After reviewing primarily English-language, peer-reviewed journal articles, we here summarize the clinical manifestations of Marburg virus disease and the results of studies in NHP showing the characteristics and progression of the disease. We also include a detailed comparison of the characteristics of the human disease relative to those for NHP. This review reveals that the disease characteristics of Marburg virus disease are generally similar for humans and 3 NHP species: cynomolgus macaques (Macaca fascicularis), rhesus macaques (Macaca mulatta), and African green monkeys (Chlorocebus aethiops).

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Figures

Figure 1.
Figure 1.
Symptoms and clinical manifestations associated with MARV. Time to onset of symptoms (human) reported are based on the estimated date of infection and symptomatology in cases from South Africa or Germany. Clinical manifestations in NHP are reported as having occurred x number of days after the animal was challenged with MARV. The range for time to onset of symptoms/clinical manifestations of MVD is similar by comparison between each species of NHP—cynomolgus, rhesus, or African green monkey—and humans. In addition, even though some human symptoms (for example, headache, sore throat) cannot be easily discerned in NHP and although some clinical signs (for example, fever) were not always measured in animal studies, common clinical signs of fever, anorexia or weight loss, lethargy or depression or decreased responsiveness, and rash or petechiae were observed consistently in humans and cynomolgus and rhesus macaques.
Figure 2.
Figure 2.
Time to death from MARV infection. The time to death for the human cases was based on the estimated date of exposure in cases from South Africa or Germany. The time to death for NHP was always calculated based on the date of challenge with MARV or RAVV. Times to death are similar for MARV or RAVV infections in humans and in each of the 3 NHP species.
Figure 3.
Figure 3.
Hematology and coagulation parameters affected by MARV.
Figure 4.
Figure 4.
Clinical chemistry parameters affected by MARV. Clinical chemistry data revealed evidence of hepatobiliary and renal damage for humans and cynomolgus and rhesus macaques infected with MARV or RAVV. In addition, an effect on the pancreas was noted for humans and rhesus monkeys; an increase in amylase is presumed, based on the diagnosis of pancreatitis.
Figure 5.
Figure 5.
MARV virus detection and measurement. For cynomolgus and rhesus macaques, MARV and RAVV titers were quantitatively measured in blood and tissues by using plaque assays. For African green monkeys, only the viral titers determined by using the TCID50 assay are reported; titers determined in guinea pigs by using the end-point dilution method are not. Viral load data in humans were available only for 4 patients from the 1967 and 1975 outbreaks. To confirm active viral infection, human specimens have been tested by using animal inoculation or immunocytochemistry historically or PCR, immunohistochemistry, or ELISA more recently.
Figure 6.
Figure 6.
Macroscopic findings associated with MARV.
Figure 7.
Figure 7.
Microscopic findings associated with MARV. Microscopic lesions of the liver, lymphoid organs, and kidney were common among humans and all 3 NHP species. Adrenal gland involvement was similar between humans and cynomolgus macaques.
Figure 8.
Figure 8.
Documentation regarding humane treatment of animals used in studies of MARV.
Figure 8.
Figure 8.
Documentation regarding humane treatment of animals used in studies of MARV.
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References

    1. Adams MJ, Carstens EB. 2012. Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2012). Arch Virol 157:1411–1422. - PMC - PubMed
    1. Adjemian J, Farnon EC, Tschioko F, Wamala JF, Byaruhanga E, Bwire GS, Kansiime E, Kagirita A, Ahimbisibwe S, Katunquka F, Jeff B, Lutwama JJ, Downing R, Tappero JW, Formenty P, Amman B, Manning C, Towner J, Nichol ST, Rollin PE. 2011. Outbreak of Marburg hemorrhagic fever among miners in Kamwenge and Ibanda Districts, Uganda, 2007. J Infect Dis 204:S796–S799. - PMC - PubMed
    1. Alves DA, Glynn AR, Steele KE, Lackemeyer MG, Garza NL, Buck JG, Mech C, Reed DS. 2010. Aerosol exposure to the Angola strain of Marburg virus causes lethal viral hemorrhagic fever in cynomolgus macaques. Vet Pathol 47:831–851. - PubMed
    1. Bausch DG, Nichol ST, Muyembe-Tamfum JJ, Borchert M, Rollin PE, Sleurs H, Campbell P, Tshioko FK, Roth C, Colebunders R, Pirard P, Mardel S, Olinda LA, Zeller H, Tshomba A, Kulidri A, Libande ML, Mulangu S, Formenty P, Grein T, Leirs H, Braack L, Ksiazek T, Zaki S, Bowen MD, Smit SB, Leman PA, Burt FJ, Kemp A, Swanepoel R. 2006. Marburg hemorrhagic fever associated with multiple genetic lineages of virus. N Engl J Med 355:909–919. - PubMed
    1. Bechtelsheimer H, Korb G, Gedigk P. 1972. The morphology and pathogenesis of ‘Marburg virus’ hepatitis. Hum Pathol 3:255–264. - PubMed

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