Role of Vaccination in Biological Disaster Prevention Conference

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

Description of Bioterrorism 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 Vaccination as a Bioterrorism Countermeasure /2

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

Why would terrorists choose to The Threat employ Biological Agents? 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 4

Selection of Medical Countermeasures THE THREAT (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 5

THE THREAT 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. 6

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

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

Smallpox General features 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 nonimmunized population Availability to terrorists unknown 9

Smallpox Clinical course of action Rash Macules Papules Onset Vesicles & Pustules Modified from Source: CDC 10

Smallpox Current smallpox vaccines 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 11

Traditional Smallpox vaccination Side effects: 1 st and 2 nd Generation vaccines Not suitable for immune compromised individuals 12

Need for safe Smallpox Vaccines 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) 13

Smallpox Utility of current smallpox vaccines 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 (? ) 14

Issues that could change the Smallpox risk/benefit ratio 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 15

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 16

Botulism Current botulism vaccines Vaccines exist (non-licensed): – Composed of botulinum toxoids – Require multiple doses for protection – Elicited antibodies block unbound toxins 17

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 18

Issues that could change the Botulism 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 19

Anthrax as a Bioterrorism Agent 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 20

Anthrax Disease 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 21

Anthrax Disease Types of Anthrax disease 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 Image courtesy of: Dr P. S. Brachman, Public Health Image Library CDC, Atlanta, Ga. 22

Anthrax Disease Inhalational Anthrax 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 Chest x-ray with widened mediastinum 22 hours before death. 23

Anthrax Disease Inhalational Anthrax – key points 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 24

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

Anthrax as a Bioterrorism Agent 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 26

Anthrax as a Bioterrorism Agent Anthrax letters — medical response 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. 27

Anthrax as a Bioterrorism Agent Anthrax letters — medical response 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). 28

Anthrax as a Bioterrorism Agent Anthrax letters — medical response “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. No person who received antibiotics, with or without vaccine, developed anthrax. 29

Anthrax as a Bioterrorism Agent 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 30

Anthrax as a Bioterrorism Agent Antibiotic-resistant Anthrax High Antibiotic Concentration Low 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. 31

Anthrax as a Bioterrorism Agent 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 postexposure use of vaccine is warranted. 32

Anthrax as a Bioterrorism Therapeutic measures to Prevent/Treat Agent 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 otherapeutic agents(? ). Lowest chance of success. 33

Protection against Anthrax ® (Anthrax Vaccine Description of Bio. Thrax in the U. S. 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 (Do. D) More than 8 million doses administered to more than 2 million U. S. Do. D 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 34

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

Conclusions Preparation for future attacks 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. 36

Conclusions Preparation for future attacks Pre-exposure immunization program Provides protection even against antibioticresistant strains of B. anthracis Military personnel Paramilitary Forces Immunize adequate numbers of critical response personnel: – – – Emergency responders Healthcare workers Laboratory personnel Investigators Decontamination workers 37

Conclusions 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 Bio. Thrax given at 0 - 2 - 4 weeks Requires stockpiles of antibiotics and vaccine readily available for rapid deployment 38

Vaccines as Bio-terrorism Countermeasures Conclusions 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 39

Conclusions Bioterrorism – Are We Prepared? 40

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