Poxvirus Research Project
Bioterrorism with variola virus concerns the biomedical community because (a) the world population is largely susceptible since routine vaccination was discontinued; (b) no treatment exists; (c) the virus is stabilize in aerosol form; (d) the virus is transmissible person-to-person; and (e) infection results in high morbidity and mortality.
Vaccination with the related vaccinia virus (VV) was a key factor in eradicating smallpox. The necessity to vaccinate an at-risk population with VV is central to preparing for the potential threat of smallpox bioterrorism. Recognized complications associated with vaccinia vaccination, especially in immunocompromised hosts (pregnant women, and infants) or people with certain skin disorders, impose serious limitations to this strategy. In past vaccination efforts, these special cases were treated with human vaccinia immune globulin (VIG) obtained from VV-immunized people. While new stocks of VIG are being generated, there are serious drawbacks to relying on a blood product. Consequently, developing therapeutic interventions to counter complications from the current vaccine and to develop a safer vaccine are paramount. As part of the MARCE efforts, the Poxvirus Research Project is working to develop vaccine candidates and new therapies by understanding and targeting poxvirus proteins recognized by the humoral immune system.
The sub-projects associated with the Poxvirus Research Project are described below.
Stuart N. Isaacs, M.D. - Project Leader
Associate Professor of Medicine
University of Pennsylvania School of Medicine, Division of Infectious Diseases
Website:
http://www.med.upenn.edu/camb/faculty/mv/isaacs.html
E-mail Address:
isaacs@mail.med.upenn.edu
Developing a subunit vaccine against smallpox (variola) virus
Eradication of smallpox (variola) by vaccination with live vaccinia virus (VV, a related pox virus) led to cessation of routine vaccination in the USA in 1972. Thus, the entire population older than 34 years is potentially susceptible to this disease.
Identifying new targets of neutralizing antibody
The heightened concern about the intentional release of variola virus has led to the need for the development of safe and effective smallpox vaccines. While the current smallpox vaccine (Dryvax) is very effective, a significant portion of the population have contraindications that would preclude them from routine vaccination. Such contraindications include common skin conditions like eczema and atopic dermatitis, cardiac disease, pregnancy, or immunodeficiencies due to medications or disease.
Developing an ectromelia virus challenge system
The emerging threat of smallpox-variola virus (VA) as a terrorist weapon has multiple implications and ramifications for the citizens of the US and the world at large.
Identifying lead antivirals to block smallpox DNA processivity and infectivity
Novel therapeutics against variola, the causative agent of smallpox, are needed for a rapid response to bioterrorism. Therapeutics can prevent smallpox spread when vaccine delivery is delayed; blunt adverse complications of vaccine administration; and protect individuals for whom the vaccine is contraindicated. Processivity factors are ideal therapeutic targets since they should possess viral specificity with minimal toxicity.
Inhibition of poxvirus resolvase
We propose to develop inhibitors of the poxvirus-encoded resolvase enzyme (A22R in vaccinia). Poxviruses are very large and carry out their replication cycles in viral "factory centers" in the cytoplasm of infected cells. Thus many of the proteins important in viral DNA metabolism are necessarily encoded in the viral genome. This includes a resolvase that cleaves DNA concatemers to yield unit length genomes.