Responding to the Threat of Bioterrorism: A Status Report on Vaccine Research in the United States Good Morning. Over the next 1 ½ hours of so I’ll be talking about some of the biological agents that are considered most concerning if utilized as a bioterrorism agent against civilian populations. I’ll mainly be touching on some of the clinical characteristics of the illnesses caused by these agents and their general medical management. Dixie E. Snider, M.D., M.P.H. Associate Director for Science Centers for Disease Control and Prevention

Biological Terrorism: Why Be Concerned Now? Low tech, low expense Multiple means of dissemination Developed as biological weapons Economic, political, religious polarization Contagiousness/lack of immunity Diseases unfamiliar/covert action easy Potential for panic/economic impact Let’s start out by just touching on why we’re so concerned about this topic these days. From a political analysis standpoint, it is felt that the make-up, goals, and motivations of terrorist groups have changed. In the past, more terrorist groups had motivations that benefited by gaining some amount of public sympathy for their cause. Committing crimes that resulted in overwhelming public outrage was generally counterproductive to their goal of gaining public support to initiate political change. However, more terrorist groups today could be defined as extremist organizations with religious, racial, or non-support seeking motivations. These groups may feel that their terrorist acts are justified by a “higher purpose” as in the case of some extremist religious or hate groups and may not be restrained by the need to gain public support for their cause. From a scientific standpoint, the breakup of the Soviet Union and its large bioweapons program may have resulted in the availability of stores of biological weapons or scientific expertise to several other nations who are seeking to develop biological weapons programs despite international regulations prohibiting such programs. Also, as scientific technology advances, it may become easier for a less sophisticated terrorist to develop and successfully use a biological weapon. Advancing technology in the field of genetics may also open up new arenas for nations or terrorists that have the desire, expertise, and financial backing to explore these possibilities. This next gentleman speaks to another issue of concern, availability. Although it may not be as easy to develop some biological agents into effective weapons, the availability of some of these agents in nature and the seemingly increased interest in exploring their potential certainly raises concern.

Biological Agents of Highest Concern Variola major (Smallpox) Bacillus anthracis (Anthrax) Yersinia pestis (Plague) Francisella tularensis (Tularemia) Botulinum toxin (Botulism) Filoviruses and Arenaviruses (Viral hemorrhagic fevers) Taking all these things into consideration, the following list of 6 biological agents were identified as agents that would be of greatest concern for public health officials if they were released on a civilian population. Identification of these agents was not based on the probability of their use, but on the impact that their use would have. In other words, being prepared for the worst makes you prepared for the more likely.

Other Potential Threats BACTERIAL Brucellosis Q fever Glanders Melioidosis Food/water borne pathogens VIRAL Viral encephalitidies TOXINS Staph Enterotoxin B Ricin Tricothecene mycotoxins UNKNOWNS Genetically altered agents New chemicals Others

Why These Agents? Infectious via aerosol Susceptible civilian populations High morbidity and mortality Person-to-person transmission (smallpox, plague, VHF) Difficult to diagnose and/or treat Previous development for BW Characteristics of these agents which help them meet agent selection considerations include: Infectious via aerosol, so enhanced potential for affecting a large group of people Most people will develop illness if exposed to the right dose, no general “inherent” immunity Kill or severely sicken people that are affected Some can expand their “initial footprint” because they are contagious All are fairly uncommon and are therefore more difficult to recognize clinically or don’t have established treatment options And last but not least, other people have also evaluated these agents and thought enough of them to further develop them as biological warfare agents. For someone that is looking around for a cheap means to cause a lot of harm, going with something that has already been evaluated or developed would make sense….

Anthrax: Overview Primarily disease of herbivores Humans contract disease by contact with infected animals or contaminated animal products Soil reservoir worldwide No person-to-person transmission of inhalational anthrax Cutaneous, gastrointestinal, and inhalational forms Inhalational form >85% mortality Our first contestant today is a spore-forming bacteria named Bacillus anthracis. This organism calls many places home and considers itself a citizen of the world as it can be found in soil throughout the world. It causes a disease called anthrax that primarily effects herbivores such as cows who come into contact with the organism through contaminated soil. In a natural setting, humans contract the disease after contact with infected animals or contaminated animal produces such as hides or meat. Anthrax has 3 clinical manifestations; cutaneous disease which occurs after contact with the spore with broken skin, intestinal anthrax, which occurs after ingestion of the spores (such as with contaminated meat), and inhalational, which occurs after inhaling the spores. Drainage from a cutaneous lesion contains the organism and could be infectious, however, inhalational anthrax is not transmitted from person-to-person.

Recognition in Florida Inhalational anthrax 63 yo male photo editor employed by AMI Onset 9/30 Fever Altered mental status Admission 10/2 CSF with gram + rods Positive blood and CSF cultures Autopsy consistent with inhalational anthrax on 10/6 63 yo male photo editor employed by AMI Onset 9/30 Fever Altered mental status Admission 10/2 CSF with gram + rods Positive blood and CSF cultures CDC notification 10/3 Autopsy consistent with inhalational anthrax on 10/6

Senator Daschle & Leahy Envelopes: Postmarked 10/9/01

Anthrax Bioterrorism Investigations, 2001-2002 1. Palm Beach County – 10/3 3. Washington, DC – 10/15 2. New York City – 10/12 4. Trenton, NJ – 10/17 Anthrax Bioterrorism Investigations, 2001-2002 5. Oxford, CT – 11/20

Bioterrorism-associated Anthrax: Inhalational and Cutaneous Cases NYC NJ Inhalational Case FL DC CT inhalational anthrax case, date of onset - 11/14 NYC envelopes 9/18* Senator envelopes 10/9* 5 4 3 Cases 2 1 9/17 9/21 9/25 9/29 10/3 10/7 10/11 10/15 10/19 10/23 10/27 Date of Onset *Postmark date of known contaminated envelopes

Anthrax: Treatment Antibiotics (combination therapy) Supportive care ciprofloxacin or doxycycline, and 1 or 2 of the following: Penicillin (if PCN susceptible), rifampin, vancomycin, ampicillin, chloramphenicol, imipenem, clindamycin, clarithromycin Supportive care Standard precautions, no need for quarantine/isolation Duration of treatment dependent on form of anthrax and types of exposures Early treatment improves prognosis Several antibiotics show in-vitro activity against organism, but only PCN, Doxy, or Cipro labeled for use. [go over some of slide]

Anthrax: Post-Exposure Prophylaxis Start oral antibiotics soon (<24 hours) after exposure Ciprofloxacin Doxycycline Amoxicillin or Penicillin (if known PCN sensitive) Antibiotics for up to 100 days without vaccine Antibiotics until 3 doses of vaccine given (0, 2, 4 weeks) ~ 40 days [Go over slide]

Smallpox: Overview 1980 - Global eradication Humans only known reservoir Person-to-person transmission (aerosol/contact) Up to 30% mortality in unvaccinated Variola virus, the agent of smallpox Routine vaccination stopped in US in 1970’s Global eradication declared by WHO in 1980 No naturally occurring disease presently Human only known reservoir Infectious by respiratory route or direct contact up to 30% mortality in unvaccinated individuals

Smallpox: Management Supportive care ?Role of antiviral agents Strict respiratory/contact isolation of patient Patient infectious until all scabs have separated Immediate vaccination of ALL close contacts All contacts within 17 days of the onset of case’s symptoms Surveillance of contacts for 17 days Currently no specific medical treatment for smallpox other than supportive care. Isolate to prevent transmission Identify and vaccinate contacts, watch for symptoms of illness

Plague: Overview Natural vector - rodent flea Mammalian hosts Rats, squirrels, chipmunks, rabbits, and carnivores About 10-15 cases/year U.S. (all forms) Mainly SW states Bubonic, pneumonic, and septicemic forms [Go over slide] Picture is wayson’s stain of peripheral blood smear, showing bipolar staining characteristic of organism CDC

Plague: Medical Management Antibiotic therapy - Gentamicin, Streptomycin, Tetracyclines, Sulfonamides, Chloramphenicol (meningitis/pleuritis) Supportive therapy Isolation and droplet precautions for pneumonic plague until sputum cultures negative Contacts of pneumonic cases and those exposed at same time as index case given chemoprophylaxis – Doxycycline, Tetracycline or TMP/SMX Vaccine no longer manufactured in the U.S. Streptomycin DOC but gent used successfully in substitution because of limited availability of streptomycin, add chloramphenicol if meningitis present [go over slide]

Tularemia: Overview Disease of Northern Hemisphere In U.S., most cases associated with rabbits/hares and ticks ~ 200 cases/year in U.S. most in South central and Western states majority of cases in summer, some in winter Low infectious dose 1 to 10 organisms by aerosol or intradermal route No person-to-person transmission Tularemia caused by Francisella tularensis. Probably disease of all of them that occurs most commonly in US. [go over slide] Low infectious dose, no transmission from person to person

Tularemia: Clinical Forms Ulceroglandular Ulcer with regional adenopathy Glandular Regional adenopathy without skin lesion Oculoglandular Painful purulent conjunctivitis with adenopathy Typhoidal Septicemia, no adenopathy Possible initial presentation for BT Pneumonic (primary or secondary) Multiple clinical forms seen but typhoidal or pneumonic presentations most likely following aerosol release.

Tularemia: Treatment/Prophylaxis Streptomycin or Gentamicin Tetracyclines Prophylaxis Fever watch for 7 days (preferable) Doxycycline or Tetracycline for 14 days if febrile Vaccine investigational, not available Recommended treatments similar to those used for plague. Treatment with Doxy or TCN require longer duration of 2 – 3 weeks because of higher rate of relapse with shorter duration treatments. Strep or gent duration about 7-10 days. Vaccine currently not available and would have essentially no role in post-exposure treatment regimen but might be useful for laboratory worker protection.

Viral Hemorrhagic Fevers (VHF): Overview Caused by several different viruses families Filoviruses (Ebola, Marburg) Arenaviruses (Lassa, Junin, Machupo, Sabia, Guanarito) Bunyaviruses Flaviviruses Natural vectors - virus dependent rodents, mosquitoes, ticks Viral hemorrhagic fevers are caused by several different virus families but the ones we’re more concerned with are the filo and arenaviruses. These include ebola, marburg, and several South American hemorrhagic fever viruses. Natural vectors/reservoirs vary and are unknown for the ebola and marburg viruses. Rodent species are the reservoirs for most of the arenaviruses.

VHF: Clinical Presentation Usual patient history Foreign travel to endemic or epidemic area in rural environment Nosocomial exposure Contact with arthropod or rodent reservoir Domestic animal blood exposure Incubation Typical 5 to 10 days (Range 2 to 16 days) Symptoms Bleeding, CNS involvement Mortality agent dependent (10-90%) Incubation periods are typically between 5-10 days and in a patient with naturally acquired VHF you will usually find a recent history of: [read slide]

Botulism: Overview Caused by toxin from Clostridium botulinum Toxin types A, B, E, associated with most human disease Most potent lethal substance known (LD = 1ng/kg) C. botulinum spores found in soil worldwide ~ 100 reported cases/year in the U.S. Infant most common (72%) Food-borne not common No person-to-person transmission Botulism is caused by the neurotoxin produced by Clostidium botulinum. Botulinum toxin is one of the most potent substances know in that a very small amount can cause lethal illness if not treated. The organism is ubiquitous and naturally acquired cases of botulism are reported in the US every year. Since botulism results from ingesting or absorbing the toxin through mucous membranes, it is not transmitted from person to person.

Botulism: Forms Foodborne Wound Infant Toxin produced anaerobically in improperly processed or canned, low-acid foods contaminated by spores Wound Toxin produced by organisms contaminating wound Infant Toxin produced by organisms in intestinal tract Inhalation botulism No natural occurrence, developed as BW weapon Botulism can result from several scenarios of botulinum toxin exposure: [go through slide]

Botulism: Clinical Presentation Incubation: 18 to 36 hours (dose dependent) Afebrile, alert, oriented; normal sensory exam Early nausea, vomiting, diarrhea Cranial Nerve symptoms Ptosis, blurry/double vision, difficulty swallowing/talking, decreased salivation Motor symptoms (progressive) Bilateral descending flaccid paralysis  respiratory paralysis Death 60% untreated; <5% treated No matter the route of exposure, the clinical presentation would be similar, however, the incubation period may be shortened with higher doses of the toxin. [quickly go through slide, point out decrease in mortality with treatment]

Botulism: Treatment/Prophylaxis Ventilatory assistance and supportive care Botulinum antitoxin Licensed trivalent equine product against types A,B, and E available from CDC Most effective if given early Antibiotics for wound botulism PCN Recovery and supportive care may be prolonged Toxoid vaccine investigational, not available Other botulinum antitoxins available as Investigational New Drugs (IND) Treatment includes ventilatory support as needed and administration of botulinum toxin. The earlier the antitoxin can be given, the better. Even with antitoxin the full recovery may take months. A toxoid vaccine has been produced by the military but is investigational. Another botulinum antitoxin that is a despeciated equine product has also been produced and is investigational. Antitoxin could also be considered for prophylaxis following a known exposure. However, there are no standard protocols for the use of antitoxin for this purpose.

Anthrax Vaccine Current U.S. vaccine (FDA Licensed) Culture supernatant containing Protective Antigen (PA) from attenuated non-encapsulated strain Protective against cutaneous (human data) and possibly inhalational anthrax (animal data) Licensed 6 dose regimen over 18 months; annual boosters 3 doses (0, 2, and 4 weeks ) appear effective for post-exposure treatment in combination with abx Limited availability [go over slide] Anthrax vaccine currently not a component of NPS. Extended oral regimen appears to be as effective as shortened oral regimen with vaccine.

Anthrax Vaccine Adverse Effects 30% or less with mild discomfort at inoculation site for up to 72 hours tenderness, redness, swelling, or itching < 2% with more severe local reactions potentially limited use of the arm for 1- 2 days Reactions more common in women Systemic reactions rare What can you expect to see following vaccination: [go over slide] Long-term adverse effects or chronic conditions have not been linked with anthrax vaccine.

New Approaches: Anthrax Vaccine Recombinant vaccines Mutant-strain vaccines Purified PA preparations + adjuvant What can you expect to see following vaccination: [go over slide] Long-term adverse effects or chronic conditions have not been linked with anthrax vaccine.

AVRP Human Reactogenicity and Immunogenicity Trial to Address Change in Route of Administration and Dose Reduction Objectives: To determine impact of AVA route of administration (SQ vs IM) on reactogenicity and immunogenicity among men and women, and To evaluate the impact of AVA dose reduction from current total of 6 doses with annual booster, to 3 doses with booster every 3 years

Anthrax Vaccine Studies Effect of different doses on immunogenicity and challenge in nonhuman primates (CDC, Battelle) Serological assays and studies of immune correlates of protection (CDC, FDA, NIH, USAMRIID, Battelle, Emory) National survey of KSA’s regarding the anthrax vaccine among military personnel (CDC, DOD, RTI) Survey of health care providers regarding the vaccine and reporting of possible adverse events (CDC, FDA, DOD) What can you expect to see following vaccination: [go over slide] Long-term adverse effects or chronic conditions have not been linked with anthrax vaccine.

Anthrax Vaccine Studies Camparative evaluation of the effect of anthrax vaccine on health-related quality of life (CDC, DOD) Retrospective study of long –term adverse effects among vaccinated mill workers (CDC) Study of hormonal correlates of adverse events among female clinical trial participants (CDC, DOD) Studies of vaccine delivery and follow-up of adverse events (CDC, DOD, NVHCN) What can you expect to see following vaccination: [go over slide] Long-term adverse effects or chronic conditions have not been linked with anthrax vaccine.

Smallpox: Current Vaccine Live Vaccinia virus (not smallpox virus) ~15 million doses in US stores ID inoculation with bifurcated needle (scarification) Pustular lesion/induration surrounding central scab/ulcer 6-8 days post-vaccination Low grade fever, axillary lymphadenopathy Scar (permanent) demonstrates successful vaccination Immunity not life-long [go over current vaccine and how to vaccinate] Certain type of site reaction indicates successful vaccination Immunity wanes, really good for about 5 years if vaccinated only once, waning protection for up to 10 year Longer protection if vaccinated more than once (longer lasting high neutralizing antibody titer) WHO

Smallpox Vaccination: Complications Approximately 25AR’s/100,000 vaccinations Most common Inadvertent inoculation (skin, eye, etc.) Less Common Generalized vaccinia Post-vaccination encephalitis (2.8/million) Fetal vaccinia Eczema vaccinatum (4.5/million) Vaccinia necrosum (0.7/million) Primary vaccination - 1 death/million Revaccination - 0.2 deaths/million Although considered a safe vaccine, some complications can occur. Generally about 25 AE’s (mild to severe)/100,000 vaccinations. Most common is accidental transfer of virus from vaccine site to another area of body with resultant lesion. Usually only of concern if involves the eye because of edema, possible keratitis, etc. Other less common AE [read off] Generalized vaccinia usually mild, patient usually not sick, only requires treatment if severe and pt. Toxic appearing Death following vaccination usually due to encephalitis or vaccinia necrosum

Smallpox: Vaccinia Immune Globulin (VIG) Treatment of adverse reactions (AR) Post-exposure prophylaxis Pregnant patients (VIG + Vaccinia vaccine) Eczema (VIG + Vaccina vaccine) Immunocompromised patients, No consensus (VIG alone vs. VIG + Vaccinia vaccine) Current supplies very limited – reserved for treatment of severe AR’s, not prophylaxis Go over slide

Other Vaccines Plague Vaccine Tularemia Vaccine Used effectively in WWII and Vietnam May not protect against aerosol infection Very reactogenic Tularemia Vaccine Agent developed for BW Questionable efficacy [go over slide]

Other Vaccines Viral Hemorrhagic Fevers Botulism Toxin Vaccines at early stages of development Botulism Toxin Pentavalent toxoid available under IND Local reactions increases as number of doses increase Types F and G toxoids absent High cost [go over slide]

Bioterrorism Vaccine Issues Should we invest in developing these vaccines? Who has responsibility for R&D and production– ie, roles of government, academia, private industry developing and evaluating vaccines for BT threats? Impediments to R&D and production – select agent rule, limited facilities, limited resources How can we assure R&D will not lead to unintended adverse effects? How do we set priorities among the agents?

Bioterrorism Vaccine Issues How do we determine efficacy? Role of animal models and in vitro studies How will we obtain safety data prior to licensure and how much will be enough? How will we organize and implement safety and efficacy studies post-licensure? How will we develop protocols and consent forms? Who should be involved in the review, how to we engage them, and how do the IRBs assimilate and incorporate them? For licensed products, will “off-label” use be permitted?. Who has responsibility for developing and evaluating vaccines for BT threats? Would importation of a vaccine unlicensed in the U.S. ever be considered?

Bioterrorism Vaccine Issues Who will pay for the purchase and distribution the vaccines? Who will distribute and administer the vaccines? How will we ensure appropriate and fair distribution? How will guidelines for use of vaccines be developed? Should vaccine be stockpiled or administered or is a combination approach the most appropriate Who should be targeted for vaccine and when should they be vaccinated (e.g., pre-exposure vs. post-exposure)?

Bioterrorism Vaccine Issues Should vaccination be mandatory or permissive and how does risk of attack and necessity of quarantine affect that decision? Can we maintain the principle of autonomy in such an environment? How can we obtain true informed consent in a situation in which risk data is considered protected by national security concerns? Who assumes liability for vaccine-related injury?