Chapter 23 Lassa virus. Lassa virus is a RNA virus belonging to the family of Arenaviridae. As the causative agent of

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1 Chapter 23 Lassa virus 23.1 General overview of Lassa virus and hemorrhagic fever Lassa virus is a RNA virus belonging to the family of Arenaviridae. As the causative agent of hemorrhagic fever, Lassa virus infects more than 200,000 people per year causing more than 3,000 deaths with a mortality rate of about 15% among the hospitalized cases (Djavani et al. 2000). The U.S. Centers for Disease Control and Prevention have classified Lassa virus as a Category A bioterrorism agent for public health preparedness. Hemorrhagic fever is highly fatal disease mostly found in West Africa. The disease has an acute phase lasting 1 to 4 weeks, characterized by fever, skin rash with hemorrhages, sore throat, headache and diarrhea. It has been reported that Lassa virus infects more than 200,000 people per year with a mortality rate of about 15% among the hospital cases. Transmission of Lassa fever by direct person-to-person contact can occur via virus-contaminated blood, pharyngeal secretion, and urine of patients Summary Data Jahrling et al. (1982) exposed Hartley guinea pigs (450 to 600g) to Lassa virus via subcutaneous route. Lassa virus strain Josiah was isolated in 1976 from the serum of a 40-year-old man in Sierra Leone, Africa. Stephenson et al. (1984) exposed Hartley guinea pigs (180 to 300g) to aerosolized Lassa virus strain Josiah of 4.5 µm or less in diameter generated by dynamic aerosol aerators.

2 Table Summary of the lassa virus data and best fits Experiment number 1 Reference Stephenson et al., 1984 Host type/patho gen strain guinea pig/ Josiah strain Route /# of Doses Dose Unit Response Inhalation/4 PFU death Best Fit Model Beta- Optimize d Paramete r(s) α = N 50 = Jahrling et al., 1982 guinea pig/ Josiah strain Subcutaneous /6 PFU death Exponential k= The data from different experiments were not considered for pooling because of very different exposure routes.

3 23.3 Optimized Models and Fitting Analyses Output for experiment 1. Table 23.2: Guinea pig/ Josiah strain model data Dose Dead Survived Total 5.37E E E E Stephenson et al., Table Goodness of Fit and Model Selection Model Deviance DF Exponenti al Beta χ ,1 p- value E χ ,m-k p-value Beta- provides significantly acceptable fit Table 23.4 Optimized parameters for the best fitting (Beta ), obtained from 10,000 bootstrap iterations Parameter MLE Estimate Percentiles 0.5% 2.5% 5% 95% 97.5% 99.5% α N 50 14, (spores) 14, E E+19 inf Figure 23.1 Parameter scatter plot for beta model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters. Figure 23.2 beta model plot, with confidence bounds around optimized model

4 Output for experiment 2. Table 23.5: guinea pig/ Josiah strain model data Dose Dead Survived Total 2.40E E E E E E Jahrling et al., Table Goodness of Fit and Model Selection Model Deviance DF Exponenti al Beta E Exponential is the best fitting model χ ,1 p- value χ ,m-k p-value Table 23.7 Optimized parameters for the best fitting (Beta ), obtained from 10,000 bootstrap iterations Parameter MLE Estimate Percentiles 0.5% 2.5% 5% 95% 97.5% 99.5% k (spores) Figure 23.3 Parameter histogram for exponential model (uncertainty of the parameter) Figure 23.4 Exponential model plot, with confidence bounds around optimized model

5 23.4. Summary Noting a significant difference of between the inhalation (1.4x10 4 pfu) and subcutaneous (0.2 pfu) routes has been identified, which suggests a substantial variation of virulence with infection site. This could also attribute to the difference between out-bred and in-bred origins. The very low for the subcutaneous route should be due to the uncertainties of dose counting in the original study. References Djavani, M., C. Yin, L. Xia, I. Lukashevich, C. Pauza and M. Salvato (2000). "Murine immune responses to mucosally delivered Salmonella expressing Lassa fever virus nucleoprotein." Vaccine 18(15): Jahrling, P. B., S. Smith, H. R.A. and J. B. Rhoderick (1982). "Pathogenesis of Lassa virus infection in guinea pigs." Infection and Immunity 37(2): Stephenson, E., A. Larson and J. Dominik (1984). "Effect of environmental factors on induced lassa virus infection." Journal of Medical Virology 14: