Cowpox, Camelpox, Monkeypox, Smallpox: all members of the orthopox family of infectious diseases and all of interest to the professionals in public health. The following are two abstracts of CBMTS VIII presentations.

Likelihood of Smallpox Recurrence

Jennifer Gaudioso1; Tim Brooks2; Katsuhisa Furukawa3, Daniel O. Lavanchy4, David Friedman5; and
Erik D. Heegaard6

1International Biological Threat Reduction Program, Sandia National Laboratories, NM, US
2Novel & Dangerous Pathogens Department, Health Protection Agency, Centre for Emergency Preparedness & Response, Porton Down, Salisbury, UK
3Research Institute of Science and Technology for Society, Japan Science and Technology Agency, Tokyo, Japan
4Communicable Disease Surveillance and Response, World Health Organization, Geneva, Switzerland
5The Institute for National Security Studies, Tel Aviv, Israel
6Biosecurity Institute, Lyngby, Denmark

Infectious disease threats are a continuous challenge for society, and may originate from both naturally occurring and deliberately introduced pathogens and toxins. Eradicated or novel pathogens pose a particular preparedness challenge for decision makers who are faced with the question of allocating scarce public resources to address diseases that are not a current threat. Polio, 1918 influenza (no outbreaks for 90 years), SARS (no outbreaks since 2003) and smallpox are all of particular concern. Although smallpox was eliminated through a global eradication program, some experts remain concerned about the possibility that smallpox could reappear as a biological weapon.
Our discussion seeks to systematically examine the various pathways that could lead to accidental or deliberate introduction of a novel or eradicated pathogen. Six main pathways for possible reintroduction of smallpox are evaluated here: (1) biosafety incident at a known repository, (2) biosafety incident outside of a known repository, (3) environmental resurrection, (4) biosecurity incident at a known repository, (5) illicit state biological weapons program, and (6) creation of the virus using the tools of modern biotechnology. Since reliable data are not available to enable a probabilistic assessment of the likelihoods of the six main pathways, we used influence diagrams to structure the analysis.

Current smallpox risk assessments uniformly conclude that any outbreak would constitute a potential major international security and public health challenge. The main, largely unknown, factor influencing the overall risk is the availability of the agent. While the likelihood of acquisition (a necessary prerequisite to attack) is low, scientific advances include the synthesis of eradicated, soon-to-be eradicated or inaccessible agents, such as 1918 influenza, polio virus and smallpox, respectively, and become a main driver influencing the likelihood of attack or accidental release, thus representing a “game-changing” event.

To date, countries' preparedness for risks associated with eradicated and/or novel pathogens relies predominately on the unavailability of these pathogens. Through a systematic analysis of possible pathways of introduction, our discussion has challenged this assumption. The likelihood of smallpox being reintroduced (accidently or deliberately) is unknown, but non-zero and is increasing with time. With the advent of de-novo synthesis, the risk of smallpox recurrence becomes a real and present danger and changes the overall risk assessment.

Given the many ways of obtaining dangerous pathogens and the number of additional steps required to use them as weapons, synthetic genomics makes a rather limited contribution to today's general bioterrorist threat. However, when looking at some of the most feared and potent biological agents, inaccessibility is the main defense limiting nefarious use and this barrier is destined to crumble with the ongoing rapid advancement of the life sciences.

Evaluation of Safety of Three Smallpox Vaccines in Immune Competent and Immune Deficient Mouse Models

Dr. Alex Lyubimov, Toxicology Research Laboratory, University of Illinois at Chicago, 808 S. Wood Street, Chicago, Illinois 60612, USA
e-mail: Lyubimov@uic.edu and tel 1-312-996-2123
Matt Lindeblad, Dr. Raj Krishnaraj, Toxicology Research Laboratory, University of Illinois at Chicago, Chicago, Illinois 60612, USA
e-mail: mlindebl@uic.edu and tel 1-312-996-4467

Safer vaccines are required to protect people against the threat of bioterrorism attack (including smallpox and other potential bioterror agents). Dryvax is the standard vaccinia vaccine against smallpox in humans but is known to produce complications, especially in immune deficient populations (e.g., elderly or the very young). In our studies the Dryvax vaccine was compared with a MVA vaccine candidate, a highly attenuated strain of vaccinia virus, in immune compromised and immune competent mouse models.

Initially, SCID/beige, NIH III and RAG2 transgenic immunodeficient mice were used to compare the safety of smallpox vaccines. Female BALB/c mice intraperitoneally injected with cyclophosphamide were used in a follow-up study as the pharmacologically-immunosuppressed mouse model.

The RAG2 mice followed by NIH III mice appeared to be the most sensitive immunodeficient mouse strain to Dryvax vaccine based on mortality, clinical signs and skin lesions. MVA was significantly safer compared to Dryvax in all three transgenic immune suppressed models.

Vaccination of immunocompetent and chemically immunosuppressed mice with MVA NR-70 and Dryvax vaccines produced clinical signs and decreased body weight gains only in the immunosuppressed animals. Local lesions (only in the immunosuppressed mice dosed with the highest level of Dryvax), some detectable viral levels in blood (day 2 only) and in ovaries, and induction of INF production after immunization with both vaccines were seen. It appears that Dryvax produced a more prominent effect (induced local lesions, higher viral PFU counts in blood and ovaries) and slightly higher (and longer) INF production, more evident in immunosuppressed animals.

Acknowledgement: This work was funded by the NIAID contract No. HHSN266200400093I, Project Officer, Blaire Osborn.

Editorís Notes:

How serious is the smallpox threat? According to the Centers for Disease Control and Prevention (CDC-Atlanta): The deliberate release of smallpox as an epidemic disease is regarded as a possibility, and the US is taking precautions to deal with this possibility. Smallpox is classified as a Category A agent and Category A agents are believed to pose the greatest potential threat for adverse public health impact and have a moderate to high potential for large-scale dissemination. The public is generally more aware of category A agents, and broad-based public health preparedness efforts are necessary. (Other Category A agents are anthrax, plague, botulism, tularemia, and viral hemorrhagic fevers.) CDC canít say with certainty how a smallpox attack might occur, but CDC does know how smallpox is normally transmitted, i.e., through person-to-person contact, more rarely through contact with materials contaminated with the smallpox virus, and rarely through airborne contagion in enclosed settings. DHHS/BARDA does have a contract with Bavarian Nodic to deliver 20 million doses of its Imvamune smallpox vaccine to the US government for its Strategic National Stockpile (SNS). This vaccine is made with a modified vaccinia ankara which is reported to be a safer alternative to the smallpox vaccine presently in storage. The smallpox concerns can never be fully addressed until such time as we understand how much weaponized smallpox agent was produced, how much was destroyed, how much was stolen and how much lingers at and around any of the testing grounds, i.e., from Turkmenistan to Kazakhstan and points in between. And lastly and very importantly - where all scientists working these projects over the many years of the cold war, currently are.





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