Conference on Chemical Disaster Management, Pipelines, Storages & Medical Preparedness New Delhi, India 12 February, 2009 Role of Vaccination in Biological

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, PhDVice President, Medical Affairs

Emergent BioDefense Operations Lansing

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


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


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


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


Vaccines as Medical Countermeasures Vaccines as Medical Countermeasures Against Biological AgentsAgainst 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


CDC Category A agentsThe 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

PROPRIETARY AND CONFIDENTIAL


Variola

Variola virus infection of humansSmallpox


General featuresSmallpox

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


Clinical course of actionSmallpox

Rash OnsetRash Onset

Modified from

Macules

Papules

Vesicles &

Pustules

Source: CDC


Current smallpox vaccinesSmallpox

Vaccines exist - 1st and 2nd generation:– Live (vaccinia), effective with single dose

– Applied by scarification

– Not suitable for immune compromised individuals

– Issues with safety


Traditional Smallpox

vaccination

Side effects: 1st and 2nd Generation vaccines

Not suitable for immune compromised individuals


New developments: MVA as smallpox vaccine

3rd 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


Utility of current smallpox vaccinesSmallpox

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 (?)


Issues that could change the risk/benefit ratioSmallpox

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


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


Botulism Current botulism vaccines

Vaccines exist (non-licensed):

– Composed of botulinum toxoids

– Require multiple doses for protection

– Elicited antibodies block unbound toxins


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


BotulismIssues 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


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


Agent


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


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.


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

Spore

Bacteria

Spore

Bacteria

Remaining spores Spore

Bacteria


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


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


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


Agent


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


Agent


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).



Agent


“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.


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


Agent


AntibioticConcentration

High

Low

Antibiotic-resistant Anthrax


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.


ANTHRAXANTHRAXIssues That Issues That HaveHave Changed Risk / Benefit 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.


Agent


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.


Agent


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.


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

DoD HHS

Emergency responders

Other Key Target Groups

Foreign governments

Private industry

Protection against Anthrax


Preparation for future attacksConclusions

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.


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


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


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


Bioterrorism –

Are We Prepared?

Conclusions

Asia Pacific Biosecurity

Association Manila

22-24 April 2008

Vaccination as a Bioterrorism Countermeasure

A. Thomas Waytes, MD, PhDVice President, Medical Affairs

Emergent BioDefense Operations Lansing

Documents

Conference on Chemical Disaster Management, Pipelines, Storages & Medical Preparedness New Delhi, India 12 February, 2009 Role of Vaccination in Biological