Lassa virus: Dose Response Models

Lassa virus

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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 . 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.

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Summary Data

Jahrling et al. 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. 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.

Table 5.1. Summary of the lassa virus data and best fits Experiment number Reference Host type/pathogen strain Route/number of doses Dose units Response Best-fit model Best-fit parameters LD50 1 Stephenson et al., 1984 guinea pig/ Josiah strain Inhalation/4 PFU death Beta-Poisson α = 0.079, N50 = 14253 14253 2* Jahrling et al., 1982 guinea pig/ Josiah strain Subcutaneous/6 PFU death Exponential k = 2.95 0.24

The data from different experiments were not considered for pooling because of very different exposure routes.

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^*Recommended Model

It is recommended that experiment 2 should be used as the best dose response model. Subcutaneous exposure is much more infective than the inhalation in this case so that it should receive more attention in terms of emergency preparedness and public intervention.

Optimized Models and Uncertainty and Fitting Analyses

Output for experiment 1.

Table 5.2: Guinea pig/ Josiah strain model data Dose Dead Survived Total 5.37E+03 4 4 8 7.24E+02 3 5 8 4.80E+01 1 7 8 5.00E+00 1 7 8 Stephenson et al., 1984.

Table 5.3: Goodness of Fit and Model Selection Model Deviance Δ Degrees of Freedom χ20.95,1 p-value χ20.95,m-k p-value Exponential 14.44 13.80 3 3.84 2.00E-04 7.81 0.0024 Beta Poisson 0.63 2 5.99 0.729 Beta Poisson is best fitting model

Table 5.4: Optimized parameters for the best fitting (beta Poisson), obtained from 10,000 bootstrap iterations Parameter MLE Estimate Percentiles 0.50% 2.5% 5% 95% 97.5% 99.5% α 0.079 -- -- -- -- -- -- N50 14,253 -- -- -- -- -- -- LD50(spores) 14,253 0.21 0.92 2.90 1.03E+15 2.84E+19 inf

Figure 5.1 Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.

Figure 5.2 beta Poisson model plot, with confidence bounds around optimized model

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Output for experiment 2.

Table 5.5: Guinea pig/ Josiah strain model data Dose Dead Survived Total 2.40E+05 5 0 5 2.40E+03 15 0 15 2.40E+01 10 0 10 2.00E+00 10 0 10 2.00E-01 4 6 10 2.00E-02 1 9 10 Jahrling et al., 1982.

Table 5.6: Goodness of Fit and Model Selection Model Deviance Δ Degrees of Freedom χ20.95,1 p-value χ20.95,m-k p-value Exponential 0.42 6.00E-04 5 3.84 0.98 11.07 0.99 Beta Poisson 0.42 4 9.49 0.98 Exponential is best fitting model

Table 5.7: Optimized parameters for the best fitting (Exponential), obtained from 10,000 bootstrap iterations Parameter MLE Estimate Percentiles 0.50% 2.5% 5% 95% 97.5% 99.5% k 2.95 1.37 1.61 1.65 5.43 6.48 8.62 LD50(spores) 0.24 0.080 0.11 0.13 0.42 0.43 0.50

Figure 5.3 Parameter histogram for exponential model (uncertainty of the parameter)

Figure 5.4 Exponential model plot, with confidence bounds around optimized model

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Summary

Noting a significant difference of LD₅₀ between the inhalation (1.4x10⁴ 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 LD₅₀ for the subcutaneous route should be due to the uncertainties of dose counting in the original study.

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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): 1543-1554.

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): 771-778.

Stephenson, E., A. Larson and J. Dominik (1984). "Effect of environmental factors on induced lassa virus infection." Journal of Medical Virology 14: 295-303.