BW-ch21.pdf

Medical Countermeasures

Chapter 21

MEDICAL COUNTERMEASURES

Janice M. Rusnak, MD * ; ellen F. BouDReau, MD † ; Matthew J. hepBuRn, MD ‡ ; JaMes w. MaRtin, MD, Facp § ;

a n d sina BavaRi, p h D ¥

INTRODUCTION

BACTERIAL AND RICkETTSIAL DISEASES

Anthrax

Tularemia

Plague

Glanders and Melioidosis

Brucellosis

Q Fever

VIROLOGy

Alphaviruses

Smallpox

Viral Hemorrhagic Fevers

TOxINS

Botulinum Toxin

Staphylococcal Enterotoxin B

Ricin

SUMMARy

* Lieutenant Colonel, US Air Force (Ret); Research Physician, Special Immunizations Program, Division of Medicine, US Army Medical Research

Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Maryland 21702; formerly, Deputy Director of Special Immunizations Program, US

Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Maryland

† Chief, Special Immunizations Program, Division of Medicine, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort

Detrick, Maryland 21702

‡ Major, Medical Corps, US Army; Infectious Diseases Physician, Division of Medicine, US Army Medical Research Institute of Infectious Diseases,

1425 Porter Street, Fort Detrick, Maryland 21702

§ Colonel, Medical Corps, US Army; Chief, Operational Medicine Department, US Army Medical Research Institute of Infectious Diseases, 1425 Porter

Street, Fort Detrick, Maryland 21702

¥ Chief, Department of Immunology, Target Identification and Translational Research, US Army Medical Research Institute of Infectious Diseases, 1425

Porter Street, Fort Detrick, Maryland 21702

465

Medical Aspects of Biological Warfare

INTRODUCTION

countermeasures against bioterrorism to prevent or

limit the number of secondary infections or intoxica-

tions include ( a ) early identification of the bioterrorism

event and persons exposed, ( b ) appropriate decontami-

nation, ( c ) infection control, and ( d ) medical counter-

measures. the initial three countermeasures are non-

medical and discussed in other chapters. this chapter

will be restricted to medical countermeasures, which

include interventions such as active immunoprophy-

laxis (ie, vaccines), passive immunoprophylaxis (ie, im-

munoglobulins and antitoxins), and chemoprophylaxis

(ie, postexposure antibiotic prophylaxis) (tables 21-1

and 21-2). Medical countermeasures may be initiated

either before an exposure (if individuals are identified

as being at high risk for exposure) or after a confirmed

exposure event. Because medical countermeasures

TABLE 21-1

VACCINES, VACCINE DOSAGE SCHEDULES, AND POSTVACCINATION PROTECTION

Vaccine

Primary Series Protection

Booster Doses

anthrax (0.5 ml sQ)

Days 1, 14, 28 3 weeks after 3rd vaccine dose

annual boosters after

Months 6, 12, 18

dose 6 of vaccine

tularemia * , †

Day 0

“take” after vaccination

every 10 years †

(15 punctures pc)

Q fever ‡ (0.5 ml sQ)

Day 0

3 weeks after vaccination

none

vee c-83 * , § (0.5 mL SQ) Day 0 Titer ≥ 1:20

None (boost with TC-84) ¥

vee tc-84 § (0.5 mL SQ) Day 0 Titer ≥ 1:20

As needed per titer ¥

eee ¶ (0.5 mL SQ)

Days 0, 7, 28 Titer ≥ 1:40

As needed per titer ¥

wee ¶

Days 0, 7, 28 Titer ≥ 1:40

As needed per titer ¥

Yellow fever * (0.5 ml sQ)

Day 0

4 weeks after vaccination

every 10 years

smallpox * ,** (3 punctures

Day 0

evidence of a “take” (vesiculo-papular

1, 3, or 10 years **

pc for primary vaccination)

response); scab resolved (day 21-28 after

vaccination)

RVF (1 mL SQ)

Days 0, 7, 28, 180 Titer ≥ 1:40 after dose 3

As needed per titer ¥

Junin * , †† (0.5 ml iM)

Day 0

4 weeks after vaccination

none

tBe §§ (0.5 ml sQ)

Days 0, 30

2 weeks after 2nd vaccine dose

every 3 years

pBt ¥¥ (0.5 ml sQ)

Days 0, 14, 84, potential protection within 4 weeks of 3rd Booster dose at 12 months

and month 6

vaccine dose (antitoxin titers no longer

and then yearly

obtained)

* live vaccine.

† investigational live attenuated tularemia nDBR 101 vaccine. Booster doses currently recommended every 10 years, although immunity

may persist longer.

‡ investigational inactivated freeze-dried Q Fever nDBR 105 vaccine.

§ investigational live attenuated tc-83 nDBR 102 vee vaccine is given as a one-time injection. pRnt 80 titers were obtained after vaccination

and yearly to assess for adequate titers. if pRnt 80 titers fell below a predetermined level, another investigational vaccine, the inactivated

c-84 tsi-GsD-205 vee vaccine, was given to boost titers.

¥ pRnt 80 titers. titers are obtained within 28 days of the primary series and yearly afterward to assess immune response. Booster doses for

eee were administered as 0.1 ml intradermally.

¶ investigational inactivated tsi-GsD-104 eee and tsi-GsD-210 wee vaccines.

** Booster doses are administered as 15 punctures pc, given every 10 years, but may be recommended more frequently if high risk of expo-

sure (ie, smallpox outbreak, laboratory workers). laboratory workers are given booster doses every 3 years if working with monkeypox

and yearly if working with variola (variola research only at cDc).

†† investigational live attenuated ahF virus vaccine (candid 1).

§§ investigational FsMe-iMMun inject vaccine.

¥¥ investigational botulinum pentavalent (aBcDe) botulinum toxoid.

CDC: Centers for Disease Control and Prevention; EEE: eastern equine encephalitis; IM: intramuscular; MA: microagglutination titer; PBT:

pentavalent botulinum toxoid; PC: percutaneous; PRNT 80 : 80% plaque reduction neutralization titer; RVF: Rift Valley fever; SQ: subcutane-

ous; TBE: tick-borne encephalitis; VEE: Venezuelan equine encephalitis; WEE: western equine encephalitis

466

Medical Countermeasures

TABLE 21-2

POSTExPOSURE ANTIBIOTIC PROPHyLAxIS REGIMENS

Agent

Antibiotic

Duration of Treatment

Bacillus anthracis * Ciprofloxacin, doxycycline, or penicillin (if sensitive) Vaccinated: 30 days (aerosol)

Unvaccinated: 60 days (aerosol)

Yersinia pestis

Doxycycline or ciprofloxacin

7 days

Francisella tularensis Doxycycline or ciprofloxacin

14 days

Burkholderia mallei Doxycycline, trimethoprim-sulfamethoxazole,

14 days (consider 21 days) †

augmentin, or ciprofloxacin

14 days (consider 21 days) †

B pseudomallei

Doxycycline, trimethoprim-sulfamethoxazole

(possibly ciprofloxacin)

Brucella

Doxycycline plus rifampin

21 days

Coxiella burnetii

Doxycycline

7 days (not to be given before day 8 after

exposure because it may only prolong the

incubation period)

* advisory committee on immunization practices membership notes no data on postexposure prophylaxis for preventing cutaneous anthrax

but suggests 7- to 14-day course of antibiotics may be considered.

† no clinical data to support

may be associated with adverse events, the recommen-

dation for their use must be weighed against the risk

of exposure and disease. vaccines, both investigational

and approved by the Food and Drug administration

(FDa), are available for some bioterrorism agents. in

the event of a bioterrist incident, preexposure vaccina-

tion, if safe and available, may modify or eliminate the

need for postexposure chemoprophylaxis. however,

preexposure vaccination may not be possible or practi-

cal in the absence of a known or expected release of a

specific bioterrorist agent, particularly with vaccina-

tions that require booster doses to maintain immunity.

in these cases, chemoprophylaxis after identifying an

exposure may be effective in preventing disease. any

effective bioterrorism plan should address the logistics

of maintaining adequate supplies of drugs and vac-

cines, as well as personnel to coordinate and dispense

needed supplies to the affected site.

although the anthrax and smallpox vaccines are

both FDa approved, potential bioterrorism agents have

only investigational vaccines that were developed and

manufactured over 30 years ago. these vaccines have

demonstrated efficacy in animal models and safety in at-

risk laboratory workers; however, they did not qualify

for FDa approval because studies to demonstrate their

efficacy in humans were deemed unsafe and unethical.

although these vaccines can be obtained under investi-

gational new drug (inD) protocols at limited sites in the

united states, the vaccines are in extremely limited sup-

ply and are declining in immunogenicity with age.

under the FDa animal rule instituted in 2002, ap-

proval of vaccines can now be based on demonstration

of efficacy in animal models alone, if efficacy studies

in humans would be unsafe or unethical. this rule

has opened the opportunity to develop many new

and improved vaccines, with the ultimate goal of FDa

licensure. vaccine development generally is a long

process, requiring 3 to 5 years to identify a potential

vaccine candidate and conduct animal studies to test

for vaccine immunogenicity and efficacy, with an ad-

ditional 5 years of clinical trials for FDa approval and

licensure. FDa vaccine approval then takes from 7 to

10 years, so vaccine replacements are not expected to

be available in the near future.

BACTERIAL AND RICkETTSIAL DISEASES

Anthrax

spores by ingesting contaminated soil. humans can

become infected through skin contact, ingestion, or

inhalation of B anthracis spores from infected animals

or animal products. anthrax is not transmissible from

person to person. the infective dose for inhalational

anthrax based on nonhuman primate studies is esti-

mated to be 8,000 to 50,000 spores. 1,2 the 2001 anthrax

anthrax is caused by Bacillus anthracis, a spore-

forming, gram-positive bacillus. associated disease

may occur in wildlife such as deer and bison in the

united states but occurs most frequently in domestic

animals such as sheep, goats, and cattle, which acquire

467

Medical Aspects of Biological Warfare

incident suggests that inhalational anthrax may result

from inhalation of relatively few spores with exposure

to small particles of aerosolized anthrax. 3 the stability

and prolonged survival of the spore stage makes B

anthracis an ideal agent for bioterrorism.

(toxinogenic, nonencapsulated v770-np1-R), that

produces predominantly pa in relative absence of

other toxin components such as lethal factor or edema

factor. 9,11 the filtrate used to produce ava is adsorbed

to aluminum hydroxide (amphogel [wyeth labora-

tories, Madison, nJ]) as an adjuvant and contains pa,

formaldehyde, and benzethonium chloride, with trace

lethal factor and edema factor components. 11

ava is given as subcutaneous injections (in the

upper deltoid muscle) of 0.5 ml at 0, 2, and 4 weeks,

followed by injections at 6, 12, and 18 months, and

then yearly boosters. vaccine breakthroughs have been

reported in persons who received only two doses of

vaccine, but infections in those who received all three

initial doses (and are current on subsequent primary

and booster doses) are uncommon. the few published

reports of breakthroughs occurred with use of the

earlier, alum-precipitated anthrax vaccine and within

days before the scheduled 6-month vaccine dose (dose

4), when antibody titers have been demonstrated to

be low. 8,12

evidence suggests that both humoral and cellular

immune responses against pa are critical to protec-

tion against disease after exposure. 9,13,14 vaccinating

rhesus macaques with one dose of ava elicited anti-

pa immunoglobulin (ig) M titers peaking at 2 weeks

after vaccination, igG titers peaking at 4 to 5 weeks,

and pa-specific lymphocyte proliferation present at 5

weeks. 15 approximately 95% of vaccinees seroconvert

with a 4-fold rise in anti-pa igG titer after three doses

of vaccine. 13,16 although animal studies have demon-

strated transfer of passive immunity from polyclonal

antibodies, 17 the correlation of protection against an-

thrax infection with a specific antibody titer has not

yet been defined. 13

Both the alum-precipitated vaccine and ava dem-

onstrated efficacy in animal models against aerosol

challenge. 6,7,10,13-15,18-20 a total of 52 of 55 monkeys (95%)

given two doses of anthrax vaccine survived lethal

aerosol challenge without antibiotics. 21 Because spore

forms of B anthracis may persist for over 75 days after

an inhalational exposure, vaccination against anthrax

may provide more prolonged protection than post-

exposure antibiotic prophylaxis alone. 22,23 however,

vaccination after exposure alone was not effective in

preventing disease from inhalational anthrax. vaccina-

tion of rhesus monkeys at days 1 and 15 after aerosol

exposure did not protect against inhalational anthrax (4

x 10 5 spores, which is 8 median lethal doses) resulting

in death in 8 of the 10 monkeys. however, all rhesus

monkeys given 30 days of doxycycline in addition to

postexposure vaccination survived. 24 Recent studies

indicate that a short course of postexposure antibiot-

ics (14 days) in conjunction with vaccination provides

Vaccination

History of the anthrax vaccine. in 1947 a factor

isolated from the edema fluid of cutaneous B anthracis

lesions was noted to successfully vaccinate animals. 4

this factor, identified as the protective antigen (pa),

was subsequently recovered from incubating B anthra-

cis in special culture medium. 5,6 this led to the develop-

ment in 1954 of the first anthrax vaccine, which was

derived from an alum-precipitated cell-free filtrate of

an aerobic culture of B anthracis. 7

this early version of the anthrax vaccine was dem-

onstrated to protect small laboratory animals 8 and

nonhuman primates from inhalational anthrax. 7 the

vaccine also demonstrated protection against cutane-

ous anthrax infections in employees working in textile

mills processing raw imported goat hair. 8 During this

study, only 3 cases of cutaneous anthrax occurred in

379 vaccinated employees, versus 18 cases of cutane-

ous anthrax and all 5 cases of inhalational anthrax that

occurred in the 754 nonvaccinated employees. Based

on these results, the vaccine efficacy for anthrax was

determined to be 92.5%. the vaccine failures were

noted in a person who had received only two doses of

vaccine, a second person who had received the initial

three doses of vaccine but failed to receive follow-up

doses at 6 and 12 months (infection at 13 months), and

a third person who was within a week of the fourth

vaccine dose (the 6-month dose), a period when titers

are known to be lower. local reactions were noted in

35% of vaccinees, but most reactions were short-lived

(generally resolving within 24 to 48 hours), with severe

reactions occurring in only 2.8% in the vaccinated

population.

Anthrax vaccine adsorbed. the current FDa-ap-

proved anthrax vaccine adsorbed (ava) was derived

through improvements of the early alum-precipitated

anthrax vaccine and involved ( a ) using a B anthra-

cis strain that produced a higher fraction of pa, ( b )

growing the culture under microaerophilic instead

of aerobic conditions, and ( c ) substituting an alumi-

num hydroxide adjuvant in place of the aluminum

potassium salt adjuvant. 9,10 originally produced by

the Michigan Department of public health, ava is

now manufactured by Bioport corporation in lan-

sing, Michigan. ava is derived from a sterile cell-free

filtrate (with no dead or live bacteria) from cultures

of an avirulent, nonencapsulated strain of B anthracis

468

Medical Countermeasures

significant protection against high dose aerosol chal-

lenge in nonhuman primates. 25

Vaccine adverse events. adverse reactions in 6,985

persons who received a total of 16,435 doses of ava

(9,893 initial series doses and 6,542 annual boosters)

were primarily local reactions. 26 local reactions (edema

or induration) were severe ( > 12 cm) in less than 1%

vaccinations, moderate (3–12 cm) in 3% vaccinations,

and mild ( < 3 cm) in 20% vaccinations. systemic reac-

tions were uncommon, occurring in less than 0.06%

of vaccines, and included fever, chills, body aches, or

nausea.

Data from the vaccine adverse event Reporting

system from 1990 to 2000, after nearly 2 million doses

of vaccine were distributed, showed approximately

1,500 adverse events reported from the vaccine. the

most frequently reported events were injection site

hypersensitivity (334), edema at the injection site (283),

pain at the injection site (247), headache (239), arthral-

gia (232), asthenia (215), and pruritus (212). only 76

events (5%) were serious, including the reporting of

anaphylaxis in two cases. 27

in an anthrax vaccine study conducted in labo-

ratory workers and maintenance personnel at the

us army Medical Research institute of infectious

Diseases (usaMRiiD) over 25 years, females were

found to be more likely than males to have injection

site reactions, edema, and lymphadenopathy. 28 initial

data also showed a decrease in the rate of local reac-

tions if the time interval between the first and second

dose was extended or if the vaccine was administered

intramuscularly. no decrease in seroconversion rates

or anti-pa igG geometric mean titers was noted with

either of these modifications of administration. Delay

of the second vaccine dose to 4 weeks (instead of 2

weeks) was associated with induration in only 1 of 10

females (10%) and subcutaneous nodules in only 4 of

10 females (40%), versus 10 of 18 (56%) and 15 of 43

(83%), respectively, when the second vaccine dose was

given at 2 weeks. 29 when ava was administered intra-

muscularly at 0 and 4 weeks, none of the 10 persons

exhibited induration or subcutaneous nodules, and

only one person developed erythema. the centers for

Disease control and prevention (cDc) is conducting

a large study to confirm these results.

protocols for managing vaccine adverse events

have not yet been evaluated in randomized trials.

however, individuals with local adverse events may

be managed with ibuprofen or acetaminophen for

pain, second-generation antihistamines if localized

itching is a dominant feature, and ice packs for severe

swelling extending below the elbow. in special cases,

to alleviate future discomfort for patients with large

or persistent injection-site reactions after subcutaneous

injection, the us army Medical command policy for

troops allows intramuscular injection to be considered

if the provider ( a ) believes intramuscular injection will

provide appropriate protection and reduce side effects,

and ( b ) informs the patient that intramuscular injection

is not FDa approved. 30

additional anthrax vaccination is contraindicated in

persons who have experienced an anaphylactic reac-

tion to the vaccine or any of the vaccine components. 22

it is also contraindicated in persons with a history of

anthrax infection because of previous observations of

an increase in severe adverse events. 22 the vaccine may

be given in pregnancy only if the benefit outweighs

the risk.

Other anthrax vaccines. an attenuated live anthrax

vaccine given by scarification or subcutaneous injec-

tion is used in the former soviet union. the vaccine is

reported to be protective in mass field trials, in which

anthrax occurred less commonly in vaccinated persons

(2.1 cases per 100,000 persons), a risk reduction of cuta-

neous anthrax by a factor of 5.4 in the 18 months after

vaccination. 31,32 a pa-based anthrax vaccine, made by

alum precipitation of a cell-free culture filtrate of a

derivative of the attenuated B anthracis sterne strain,

is currently licensed in the united kingdom. 19,33

New vaccine research. the ability to prepare puri-

fied components of anthrax toxin by recombinant tech-

nology has presented the possibility of new anthrax

vaccines. new vaccine candidates may be pa toxoid

vaccines or pa-producing live vaccines that elicit par-

tial or complete protection against anthrax infection. 19

a recombinant pa vaccine candidate given intrader-

mally or intranasally was demonstrated to provide

complete protection in rabbits and nonhuman primates

against aerosol challenge with anthrax spores. 34

Recent research has shown toxin neutralization

approaches to be protective in animal models. inter-

alpha inhibitor protein (iαip), an endogenous serine

protease inhibitor in human plasma, given to BalB/c

mice 1 hour before intravenous challenge to a lethal

dose of B anthracis , was associated with a 71% survival

rate at 7 days compared to no survivors in the control

groups. 35 one potential mechanism of action for iαip

is through the inhibition of furin, an enzyme required

for assembling lethal toxin in anthrax pathogenesis.

Chemoprophylaxis

Antibiotics. antibiotics are effective only against

the vegetative form of B anthracis (not effective against

the spore form). however, in the nonhuman primate

model of inhalational anthrax, spores have been shown

to survive for months ( < 1% at 75 days and trace

spores present at 100 days) without germination. 22-24

469

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