1. Conference on Chemical Disaster Management, Pipelines, Storages & Medical Preparedness New Delhi, India 12 February, 2009 Role of Vaccination in Biological Disaster Prevention A. Thomas Waytes, MD, PhD Vice President, Medical Affairs Emergent BioDefense Operations Lansing

2. Vaccination as a Bioterrorism Countermeasure /2 What is Bioterrorism?  Bioterrorism is the deliberate release of viruses, bacteria, or other germs (agents) used to cause illness or death in people, animals, or plants  Agents used are typically found in nature, but it is possible that they could be changed by terrorists to increase their ability to cause disease, make them resistant to current medicines, or to increase their ability to be dispersed  Biological agents can be spread through the air, through water, or in food Description of Bioterrorism

3. Vaccination as a Bioterrorism Countermeasure /3 What if? A terrorist drives by a local refinery and throws a canister full of Anthrax spores in proximity of the compound. Potential Consequences:  Refinery shut down, production stopped for decontamination  Entire oil related economy down  Total cost and length of decontamination unknown. Attack on facilities of high strategic national importance Recommendation: Immunize oil refinery/pipeline field workers and safety guards with anthrax vaccine Anthrax as a Bioterrorism Agent

4. Vaccination as a Bioterrorism Countermeasure /4 Why would terrorists choose to employ Biological Agents? The Threat  Inexpensive to produce compared to other weapons of mass destruction  Plausible deniability: dual-use equipment gives perpetrator the ability to produce either legal vaccines/pharmaceuticals or BW agents  Delayed effect: can work to an enemy’s advantage  Silently inflict damage: adversary can disseminate biological agent without being noticed

5. Vaccination as a Bioterrorism Countermeasure /5 Selection of Medical Countermeasures (i.e., Vaccines) Against Biological Agents Nature of the Biological Agent Viral v. Bacterial v. Other Contagious v. Non-contagious Disease from Infection v. Toxemia v. both Stage of Attack Pre-exposure Post-exposure Therapeutic THE THREAT

6. Vaccination as a Bioterrorism Countermeasure /6 Vaccines as Medical Countermeasures Against Biological Agents Changing conditions and/or evolving information may dramatically change the risk / benefit ratio of using a vaccine or other medical countermeasure for a given event, at a given time. THE THREAT

7. Vaccination as a Bioterrorism Countermeasure /7 CDC Category A agents The Threat  Variola major  Clostridium botulinum (botulinum toxins)  Bacillus anthracis  Yersinia pestis  Francisella tularensis  Filoviruses and Arenaviruses (e.g. Ebola virus, Lassa virus) Biological Agent(s)  Smallpox  Botulism  Anthrax  Plague  Tularemia  Viral hemorrhagic fevers Disease

8. PROPRIETARY AND CONFIDENTIAL Vaccination as a Bioterrorism Countermeasure /8 Variola Variola virus infection of humans Smallpox

9. Vaccination as a Bioterrorism Countermeasure /9 General features Smallpox  Variola: highly contagious, virulent virus  Eradicated as a natural disease in 1977, as a result of a world-wide immunization program  Routine immunization programs halted  No natural reservoir, exists in laboratories  May be useful bioterror agent against a non- immunized population  Availability to terrorists unknown

10. Vaccination as a Bioterrorism Countermeasure /10 Clinical course of action Smallpox Rash Onset Rash Onset Modified from Macules Papules Vesicles & Pustules Source: CDC

11. Vaccination as a Bioterrorism Countermeasure /11 Current smallpox vaccines Smallpox  Vaccines exist - 1 st and 2 nd generation: –Live (vaccinia), effective with single dose –Applied by scarification –Not suitable for immune compromised individuals –Issues with safety

12. Vaccination as a Bioterrorism Countermeasure /12 Traditional Smallpox vaccination Side effects: 1 st and 2 nd Generation vaccines Not suitable for immune compromised individuals

13. Vaccination as a Bioterrorism Countermeasure /13 New developments: MVA as smallpox vaccine 3 rd generation  Modified Vaccinia Ankara (MVA)  Fully attenuated, replication incompetent (no proliferation in the body)  New vaccine development status –2 Phase II trials finished –Tested in immune compromised individuals (HIV, atopic dermatitis) Need for safe Smallpox Vaccines

14. Vaccination as a Bioterrorism Countermeasure /14 Utility of current smallpox vaccines Smallpox  Pre-exposure –Vaccine highly effective –Recommended for high-risk occupations –Acceptability currently low due to adverse events  Post-exposure –Window of opportunity exists to immunize exposed persons  Therapeutic –Vaccinia immune globulin (?)

15. Vaccination as a Bioterrorism Countermeasure /15 Issues that could change the risk/benefit ratio Smallpox  Availability of a safer or more potent vaccine –e.g., MVA (Modified Vaccinia Ankara)  Knowledge that virus has been obtained by terrorists  Use of smallpox virus in attack

16. Vaccination as a Bioterrorism Countermeasure /16 Botulism General features  Caused by potent toxins from Clostridium botulinum  Disease results from binding of toxins at neuromuscular junction  Respiratory arrest requiring ventilation may occur within hours  Death may result in days  Organism is wide-spread in nature  Not contagious  Toxins may be intentionally introduced into food, beverages, or air

17. Vaccination as a Bioterrorism Countermeasure /17 Botulism Current botulism vaccines  Vaccines exist (non-licensed): –Composed of botulinum toxoids –Require multiple doses for protection –Elicited antibodies block unbound toxins

18. Vaccination as a Bioterrorism Countermeasure /18 Botulism Utility of current botulism vaccines  Pre-exposure –Vaccine effective following multiple doses –Recommended for very high-risk occupations –Impact on future effectiveness of therapeutic bot toxin products?  Post-exposure –No use  Therapeutic –Botulism immune globulin >Human: extremely limited supply >Equine: significant reactogenicity

19. Vaccination as a Bioterrorism Countermeasure /19 Botulism Issues that could change the risk/benefit ratio  Occurrence of an attack or series of attacks with botulinum toxin  Development of ample supplies of a safe, easy-to-administer anti-toxin  Development/availability of sensitive, real time toxin detection methods/technologies

20. Vaccination as a Bioterrorism Countermeasure /20 Why terrorists would choose to employ anthrax as a biological weapon?  Ease of Manufacture of Spores –Natural occurring disease: availability of spores –Inexpensive to produce compared to other weapons of mass destruction –The technology needed to produce anthrax is considered dual-use, as it has the ability to produce either legal vaccines or bioterrorism agents  Ease of Delivery of Spores –Delayed effect of anthrax spores can work to an enemy’s advantage –Damage is inflicted silently, allowing the adversary to disseminate biological agents without being noticed Anthrax as a Bioterrorism Agent

21. Vaccination as a Bioterrorism Countermeasure /21 Description of Anthrax disease  Anthrax infections occur if the spores enter the body through a cut, abrasion or open sore, (cutaneous anthrax), or by ingestion or inhalation of the spores  Once inside the body, anthrax spores germinate into bacteria that then multiply and release toxins Mechanism of anthrax bacteria  Anthrax bacteria secrete three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF)  Individually these proteins are non-toxic  If the proteins can interact on the surface of human or animal cells, they can become highly toxic Anthrax Disease

22. Vaccination as a Bioterrorism Countermeasure /22  Cutaneous anthrax –Infection caused by skin contact with live infected animals, or their hides, hair or bones –20% mortality rate if not treated  Gastrointestinal anthrax –Infection caused by eating undercooked or raw infected meat –80-90% mortality rate if not treated  Inhalational anthrax –Infection caused by breathing in airborne spores –~90% mortality rate without treatment Anthrax Disease Types of Anthrax disease Image courtesy of: Dr P.S. Brachman, Public Health Image Library CDC, Atlanta, Ga.

23. Vaccination as a Bioterrorism Countermeasure /23  Caused when spores are inhaled and deposited into the lungs  Incubation period usually 2 - 14 days, but can be prolonged by antibiotics  Mild, flu-like symptoms may follow  Replicating bacteria release toxins leading to sudden development of fever, hemorrhage, respiratory distress and shock  Some patients develop hemorrhagic meningitis  Death may follow in hours to days  Mortality rate is approximately 45-90%, even with aggressive treatment Inhalational Anthrax Chest x-ray with widened mediastinum 22 hours before death. Anthrax Disease

24. Vaccination as a Bioterrorism Countermeasure /24  Early symptoms often resemble common upper respiratory disease  Viable spores may exist in the lungs for more than 100 days before germination  Antibiotics are not effective against anthrax spores or toxins  Anthrax diseases cannot be transmitted person- to-person Anthrax Disease Inhalational Anthrax – key points

25. Vaccination as a Bioterrorism Countermeasure /25 1. Palm Beach County – 10/3 3. Washington, DC – 10/15 2. New York City – 10/12 4. Trenton, NJ – 10/17 5. Oxford, CT – 11/20 U.S. Anthrax Attacks of 2001: Overview Anthrax as a Bioterrorism Agent

26. Vaccination as a Bioterrorism Countermeasure /26 U.S. Anthrax attacks of 2001: Overview  Letters containing anthrax spores mailed on at least two different dates (Sep 18 & Oct 09)  Some letters contained warnings  Resulted in 22 cases of anthrax: 11 inhalational (5 fatal) and 11 cutaneous  Same B. anthracis strain (Ames) used in all letters Anthrax as a Bioterrorism Agent

27. Vaccination as a Bioterrorism Countermeasure /27 INITIAL PHASE  Antibiotic prophylaxis was initiated in ~ 32,000 persons to prevent inhalational anthrax.  Based on extent of known or anticipated anthrax exposure, a 60-day course was recommended for about 10,300 persons. –Ciprofloxacin, doxycycline, amoxicillin.  Surveys indicated that overall adherence was only ~44%. –Adverse events reported in 57% (16% sought medical care). –Perception of low risk for anthrax. –Fear of long-term side effects. Anthrax letters — medical response Anthrax as a Bioterrorism Agent

28. Vaccination as a Bioterrorism Countermeasure /28 ISSUE: 60-day antibiotic program may not be adequate to protect all exposed persons  Low adherence to 60-day antibiotic prophylaxis.  Non-human primate data demonstrating that inhaled spores could remain viable for >100 days.  Non-human primate data demonstrating that antibiotics were ineffective against dormant spores (some animals died once antibiotics were stopped). Anthrax letters — medical response Anthrax as a Bioterrorism Agent

29. Vaccination as a Bioterrorism Countermeasure /29 “AVAILABILITY PROGRAM”  An additional 40-day course of antibiotics was offered with an option to receive three injections of anthrax vaccine.  Administered under an investigational new drug (IND) program, requiring informed consent. Anthrax letters — medical response No person who received antibiotics, with or without vaccine, developed anthrax. Anthrax as a Bioterrorism Agent

30. Vaccination as a Bioterrorism Countermeasure /30 U.S. Anthrax attacks of 2001: Outcomes Could have been much worse if:  Some letters had not been clearly marked with warnings  Larger numbers of spores had been used  More efficient methods of dissemination had been used  Antibiotic-resistant strain(s) of B. anthracis had been used Anthrax as a Bioterrorism Agent

31. Vaccination as a Bioterrorism Countermeasure /31 Antibiotic Concentration High Low Antibiotic-resistant Anthrax Anthrax as a Bioterrorism Agent Reference: Brook I, et al. In vitro resistance of Bacillus anthracis Sterne to doxycycline, macrolides and quinolones. Int J Antimicrob Agents. 2001 Dec;18(6):559-62.

32. Vaccination as a Bioterrorism Countermeasure /32 ANTHRAX Issues That Have Changed Risk / Benefit Spores easily disseminated, re-aerosolized. Potential exposure can be much higher than anticipated. Potential lethality of small exposures. Antibiotic resistance (even to ciprofloxacin) and adherence may become critical issues. Pre-exposure and early post- exposure use of vaccine is warranted. Anthrax as a Bioterrorism Agent

33. Vaccination as a Bioterrorism Countermeasure /33 Therapeutic measures to Prevent/Treat Anthrax Pre-exposure prevention:  Use of anthrax vaccine before release occurs.  Best approach for at-risk persons. Post-exposure prevention:  Use of anthrax vaccine and antibiotics after exposure, but before symptoms occur.  Best approach for large numbers of exposed persons. Treatment of anthrax:  Use of antibiotics and other therapeutic agents(?).  Lowest chance of success. Anthrax as a Bioterrorism Agent

34. Vaccination as a Bioterrorism Countermeasure /34 Description of BioThrax ® (Anthrax Vaccine Adsorbed)  The only FDA-approved vaccine for the prevention of anthrax infection  Indicated as pre-exposure prophylaxis for use in adults who are at high risk of exposure to anthrax  30 million doses delivered under contracts with the U.S. Human Health Services (HHS) and the Department of Defense (DoD)  More than 8 million doses administered to more than 2 million U.S. DoD personnel since 1998  Safety affirmed and demonstrated for more than 30 years by more than 25 scientific studies  Recently received Marketing Authorization for India from the DCGI Protection against Anthrax in the U.S.

35. Vaccination as a Bioterrorism Countermeasure /35  Anthrax Vaccine Immunization Program (AVIP) –Active immunization –Reinstituted mandatory vaccination for personnel in high threat areas –Anticipate requirements for additional doses under a new RFP BioThrax ® — users  Strategic National Stockpile (SNS) –Civilian stockpiling –Existing contracts totaling 20 million doses delivered –Anticipate requirements for additional doses under a new RFP DoDHHS  Emergency responders Other Key Target Groups  Foreign governments  Private industry Protection against Anthrax

36. Vaccination as a Bioterrorism Countermeasure /36 Preparation for future attacks Conclusions ASSUME THE WORST:  Assume that exposure could be larger and more wide-spread than the U.S. letter attacks of 2001.  Assume that antibiotic-resistant strain(s) could be used.  Assume the potential lethal exposure to emergency responders, investigators, lab personnel, decontamination workers, etc.  Assume that attack may be undetected until victims become symptomatic.

37. Vaccination as a Bioterrorism Countermeasure /37 Preparation for future attacks Pre-exposure immunization program  Provides protection even against antibiotic- resistant strains of B. anthracis  Military personnel  Paramilitary Forces  Immunize adequate numbers of critical response personnel: –Emergency responders –Healthcare workers –Laboratory personnel –Investigators –Decontamination workers Conclusions

38. Vaccination as a Bioterrorism Countermeasure /38 Preparation for future attacks Post-exposure prophylaxis with antibiotics and vaccine:  Begin immediately upon identification of spores or first clinical diagnosis  CDC IND program calls for 60 days of antibiotics plus BioThrax given at 0 - 2 - 4 weeks  Requires stockpiles of antibiotics and vaccine readily available for rapid deployment Conclusions

39. Vaccination as a Bioterrorism Countermeasure /39 Vaccines as Bio-terrorism Countermeasures Vaccines have a critical role in bio-terrorism defense Depending on agent, vaccines may be utilized: Pre-exposure Post-exposure Therapeutic (passive immunity) Decisions to use are based on risk / benefit Changing conditions or evolving information may dramatically alter the risk / benefit of using a vaccine for a given agent at a given time Conclusions

40. Vaccination as a Bioterrorism Countermeasure /40 Bioterrorism – Are We Prepared? Conclusions

41. Asia Pacific Biosecurity Association Manila 22-24 April 2008 Vaccination as a Bioterrorism Countermeasure A. Thomas Waytes, MD, PhD Vice President, Medical Affairs Emergent BioDefense Operations Lansing