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13 : Countermeasures to the Reemergence of Smallpox Virus as an Agent of Bioterrorism

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Countermeasures to the Reemergence of Smallpox Virus as an Agent of Bioterrorism, Page 1 of 2

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Abstract:

Since the publication of 1992 Institute of Medicine (IOM) report , a factor in microbial emergence that has attracted an increasing degree of attention, is the possibility of deliberate release of pathogenic microbes for the purpose of biological warfare or bioterrorism. The factors that facilitate the spread of naturally occurring microbes would also contribute to the potential for even a small, deliberate introduction of smallpox virus to develop into a global pandemic. It is ironic that global eradication of smallpox virus, justifiably heralded as an unequivocal triumph of modem medicine, indirectly contributed to this modem vulnerability. The Department of Defense (DOD)-Health and Human Services (HHS) joint research plan addressed three scientific goals including diagnostics, vaccines, and antiviral drugs. In 1995, detection and identification assays for orthopoxviruses were predominantly immunologically based. Significant enhancements based on detection of viral genomes by PCR, coupled with emerging technologies such as 5' nuclease PCR assays capable of detecting single-base polymorphism in miniature analytical thermocycling instruments, were being developed. The second scientific objective of the DOD-HHS program was to evaluate the protective efficacies of existing smallpox vaccines against an aerosolized variola virus exposure. The third objective was development of an antiviral drug such as DNA polymerase inhibitors, reverse transcriptase inhibitors and IMP dehydrogenase inhibitors to treat smallpox patients.

Citation: Jahrling P, Zaucha G, Huggins J. 2000. Countermeasures to the Reemergence of Smallpox Virus as an Agent of Bioterrorism, p 187-200. In Scheld W, Craig W, Hughes J (ed), Emerging Infections 4. ASM Press, Washington, DC. doi: 10.1128/9781555816971.ch13
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Figures

Image of Figure 1.
Figure 1.

Fever curve and clinical highlights for cynomolgus monkeys exposed to aerosolized variola virus. (Redrawn from reference S.)

Citation: Jahrling P, Zaucha G, Huggins J. 2000. Countermeasures to the Reemergence of Smallpox Virus as an Agent of Bioterrorism, p 187-200. In Scheld W, Craig W, Hughes J (ed), Emerging Infections 4. ASM Press, Washington, DC. doi: 10.1128/9781555816971.ch13
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Image of Figure 2.
Figure 2.

Schematic illustrating the procedure for exposing primates to aerosolized MPOX. All steps are conducted in a gas-tight, class III cabinet system. The monkey's head is placed in an exposure chamber, and a Collison nebulizer generates an aerosol from a concentrated virus suspension. The concentration of the aerosol is determined by sampling the air and collecting virus on an all-glass impinger. Monkeys receive a calculated inhaled dose of 1 x 10to 3 x 10PFU based on an average inhaled volume of 300 ml/min.

Citation: Jahrling P, Zaucha G, Huggins J. 2000. Countermeasures to the Reemergence of Smallpox Virus as an Agent of Bioterrorism, p 187-200. In Scheld W, Craig W, Hughes J (ed), Emerging Infections 4. ASM Press, Washington, DC. doi: 10.1128/9781555816971.ch13
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Image of Figure 3.
Figure 3.

Composite summary of clinical signs in lethally infected cynomolgus monkeys exposed to aerosolized MPOX. Temperatures are unremarkable until plummeting immediately prior to death, corresponding to a precipitous fall in blood pressure and heart rate. Oxygen saturation (Sp0) falls from a normal level of 88% to <50% by the time animals become sick. Virus is isolated from buffy coat cells corresponding with detection of viral genomes by Taqman PCR in these cells beginning at 4 days after exposure. Virus titers of > 10PFU / g are isolated from lungs and spleens collected at necropsy.

Citation: Jahrling P, Zaucha G, Huggins J. 2000. Countermeasures to the Reemergence of Smallpox Virus as an Agent of Bioterrorism, p 187-200. In Scheld W, Craig W, Hughes J (ed), Emerging Infections 4. ASM Press, Washington, DC. doi: 10.1128/9781555816971.ch13
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Image of Figure 4.
Figure 4.

(A) Facial exanthema, ulcerative cheilitis, and gingivitis in a monkey infected with a lethal dose of MPOX at 13 days after exposure, (B) Necrotizing bronchopneumonia and fibrinous pleuritis from a monkey dying on day 13. (Hematoxylin- eosin stain; magnification, ×10.3.) (C) Severe necrosis of bronchial epithelium with expansion of the peribronchovascular interstitium by edema, inflammatory cells, and proliferating fibroblasts. Adjacent alveoli contain various amounts of fibrin admixed with inflammatory cells, necrotic cellular debris, and edema. (IHC, SAAP; magnification, x7.9.) (D) Lung with typ II pneumocyte. Note naked viroplasm, semicircular shells, formative shells containing viroplasm, intracellular mature virion, and lamellar structures. (Transmission electron microscopy; magnification, X7,900.) (E) Lymph node. MPOX antigen is concentrated in macrophages or dendritic cells of follicular germinal centers, coupled with extensive necrosis. (IHC, SAAP; magnification, ×52.1.) (F) Colon. Note extensive necrosis and MPOX antigen immunoreactivity of the gut-associated lymphoid tissue, with relatively mild involvement of overlying mucosa (IHC, IPO; magnification, X7.9.)

Citation: Jahrling P, Zaucha G, Huggins J. 2000. Countermeasures to the Reemergence of Smallpox Virus as an Agent of Bioterrorism, p 187-200. In Scheld W, Craig W, Hughes J (ed), Emerging Infections 4. ASM Press, Washington, DC. doi: 10.1128/9781555816971.ch13
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References

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1. Alibek, K. 1999. Biohazard, p. 111114. Random House, New York, N.Y.
2. Bray, M.,, M. Martinez,, D. F. Smee,, D. Kefauver,, E. Thompson,, and J. W. Huggins. 2000. Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge. J. Infect. Dis. 181:1019.
3.Centers for Disease Control and Prevention. 1998. Human monkeypox-Kasai Oriental, Democratic Republic of Congo, February 1996-0ctober 1997. JAMA 279:189190.
4.Federal Register. 1999. 21 CFR parts 314 and 601. New drug and biological drug products. Evidence needed to demonstrate efficacy of new drugs for use against lethal or permanently disabling toxic substances when efficacy studies in humans ethically cannot be conducted. Fed. Regist. 64:5396053970.
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8. Ibrahim, M. S.,, R. S. Lofts,, P. B. JahrIing,, E. A. Henchal,, V. M. Weedn,, M. A. Northrup,, and P. Belgrader. 1998. Real-time microchip PCR for detecting single base differences in viral and human DNA. Anal. Chem. 70:20132017.
9. Lane, J. M.,, F. L. Ruben,, J. M. Nell,, and J. D. Millar. 1968. Complications of smallpox vaccination. N. Engl. J. Med.281:12011208.
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11. Lederberg, J.,, R. E. Shope,, and S. Oaks. 1992. Emerging Microbial Threats. National Academy of Sciences, Washington, D.C.
12. McClain, D. J.,, S. Harrison,, C. L. Yeager,, and J. Cruz. 1997. Immunologic responses to vaccinia viruses administered by different parenteral routes. J. Infect. Dis. 175:756763.
13. Mukinda, V. B.,, G. Mwema,, M. Kilundu,. D. L. Heymann,, A. S. Khan,, and J. J. Esposito. 1997. Rc-emergence of human monkeypox in Zaire in 1996: report of the WHO Monkeypox Working Group. Lancet 349:14491450.
14. Nakano, J. H.,, and J. J. Esposito,. 1989. Poxviruses, p. 453511. In N. J. Schmidt, and R. W. Emmons (ed.), Diagnostic Procedures for Viral, Rickettsial, and Chlamydial Infections, 6th ed. Americal Public Health Association, Washington, D.C.
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Tables

Generic image for table
Table 1.

Challenge of monkeys immunized with Wyeth Dryvax vaccinia virus versus unimmunized controls

Citation: Jahrling P, Zaucha G, Huggins J. 2000. Countermeasures to the Reemergence of Smallpox Virus as an Agent of Bioterrorism, p 187-200. In Scheld W, Craig W, Hughes J (ed), Emerging Infections 4. ASM Press, Washington, DC. doi: 10.1128/9781555816971.ch13
Generic image for table
Table 2.

Challenge of monkeys immunized with TSI-GSD-241 (cell culture-derived) vaccinia virus versus unimmunized controls

Citation: Jahrling P, Zaucha G, Huggins J. 2000. Countermeasures to the Reemergence of Smallpox Virus as an Agent of Bioterrorism, p 187-200. In Scheld W, Craig W, Hughes J (ed), Emerging Infections 4. ASM Press, Washington, DC. doi: 10.1128/9781555816971.ch13
Generic image for table
Table 3.

IC50 of orthopoxvirus replication in Vero and BSC 40 cells by a series of drugs with known antiviral activity

Citation: Jahrling P, Zaucha G, Huggins J. 2000. Countermeasures to the Reemergence of Smallpox Virus as an Agent of Bioterrorism, p 187-200. In Scheld W, Craig W, Hughes J (ed), Emerging Infections 4. ASM Press, Washington, DC. doi: 10.1128/9781555816971.ch13

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