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General Overview

Lassa virus is an 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. 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. The U.S. Centers for Disease Control and Prevention have classified Lassa virus as a Category A bioterrorism agent for public health preparedness.

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. exposed Hartley guinea pigs (450 to 600g) to Lassa virus via the 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.

A significant difference in 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 be attribute to the difference between out-bred and in-bred origins. The very low LD50 for the subcutaneous route could be due to the uncertainties in dose counting in the original study.

Recommended Model

It is recommended that experiment 13 should be used as the best dose response model. Subcutaneous exposure is more infective than inhalation exposure in this case, so it should receive more attention in terms of emergency preparedness and public intervention.

Exponential and betapoisson model.jpg

 

ID # of Doses Agent Strain Dose Units Host type Μodel Optimized parameters Response type Reference
13 6 Josiah strain PFU guinea pig exponential
k = 2.95E+00
LD50/ID50 = 2.35E-01

death Jahrling, P B., et al. "Pathogenesis of Lassa virus infection in guinea pigs." Infection and Immunity. 37 (1982): 2.
15 4 Josiah strain PFU guinea pig beta-Poisson a = 7.94E-02

LD50/ID50 = 1.43E+04
N50 = 1.43E+04
death Stephenson, E H., E W. Larson, and J W. Dominik. "Effect of environmental factors on aerosol-induced Lassa virus infection." Journal of medical virology. 14 (1984): 4.
Recommended
Experiment ID:
13
# of Doses:
6
Agent Strain:
Josiah strain
Dose Units:
PFU
Host type:
guinea pig
Μodel:
exponential
Optimized parameters:
k = 2.95E+00
LD50/ID50 = 2.35E-01

Reference:
Guinea pig/ Josiah strain model data [1]
Dose Dead Survived Total
0.02 1 9 10
0.2 4 6 10
2 10 0 10
24 10 0 10
2400 15 0 15
240000 5 0 5

 

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 -0.000621 5 3.84 
1		 11.1 
0.995
Beta Poisson 0.42 4 9.49 
0.981
Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.

 

Optimized k parameter for the exponential model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
k 2.95E+00 1.35E+00 1.61E+00 1.65E+00 5.43E+00 5.90E+00 7.52E+00
ID50/LD50/ETC* 2.35E-01 9.21E-02 1.17E-01 1.28E-01 4.21E-01 4.32E-01 5.14E-01
*Not a parameter of the exponential model; however, it facilitates comparison with other models.

 

Parameter histogram for exponential model (uncertainty of the parameter)

Exponential model plot, with confidence bounds around optimized model

References

  1. Jahrling, P. B., Smith S., Hesse R. A., & Rhoderick J. B. (1982).  Pathogenesis of Lassa virus infection in guinea pigs. Infection and Immunity. 37, 2.
Experiment ID:
15
# of Doses:
4
Agent Strain:
Josiah strain
Dose Units:
PFU
Host type:
guinea pig
Μodel:
beta-Poisson
Optimized parameters: a = 7.94E-02

LD50/ID50 = 1.43E+04
N50 = 1.43E+04
Reference:
Guinea pig/ Josiah strain model data [1]
Dose Dead Survived Total
5 1 7 8
48 1 7 8
724 3 5 8
5370 4 4 8

 

Goodness of fit and model selection
Model Deviance Δ Degrees 
of freedom		 χ20.95,1 
p-value		 χ20.95,m-k 
p-value
Exponential 14.4 13.8 3 3.84 
0.000203		 7.81 
0.00237
Beta Poisson 0.633 2 5.99 
0.729
Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.

 

Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 7.94E-02 9.77E-04 9.85E-04 9.87E-04 4.57E-01 1.19E+00 5.76E+02
N50 1.43E+04 2.13E-01 9.22E-01 2.90E+00 1.82E+13 3.06E+17 2.25E+34

 

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

beta Poisson model plot, with confidence bounds around optimized model

References

  1. Stephenson, E. H., Larson E. W., & Dominik J. W. (1984).  Effect of environmental factors on aerosol-induced Lassa virus infection. Journal of medical virology. 14, 4.