MMWR - Use of Anthrax Vaccine in the United States

Recommendations and Reports / Vol. 68 / No. 4 December 13, 2019

Use of Anthrax Vaccine in the United States:

Recommendations of the Advisory Committee

on Immunization Practices, 2019

U.S. Department of Health and Human Services

Centers for Disease Control and Prevention

Morbidity and Mortality Weekly Report

Recommendations and Reports

CDC Adoption of ACIP Recommendations for MMWR

Recommendations and Reports, MMWR Policy Notes, and

Immunization Schedules (Child/Adolescent, Adult):

Recommendations for routine use of vaccines in children,

adolescents, and adults are developed by the Advisory

Committee on Immunization Practices (ACIP). ACIP is

chartered as a federal advisory committee to provide expert

external advice and guidance to the Director of CDC on

use of vaccines and related agents for the control of vaccine-

preventable diseases in the civilian population of the United

States. Recommendations for routine use of vaccines in

children and adolescents are harmonized to the greatest

extent possible with recommendations made by the American

Academy of Pediatrics (AAP), the American Academy of Family

Physicians (AAFP), and the American College of Obstetricians

and Gynecologists (ACOG). Recommendations for routine use

of vaccines in adults are harmonized with recommendations

of AAFP, ACOG, and the American College of Physicians

(ACP). ACIP recommendations approved by the CDC

Director become agency guidelines on the date published in the

Morbidity and Mortality Weekly Report (MMWR). Additional

information is available at https://www.cdc.gov/vaccines/acip.

The MMWR series of publications is published by the Center for Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention (CDC),

U.S. Department of Health and Human Services, Atlanta, GA 30329-4027.

Suggested citation: [Author names; first three, then et al., if more than six.] [Title]. MMWR Recomm Rep 2019;68(No. RR-#):[inclusive page numbers].

Centers for Disease Control and Prevention

Robert R. Redfield, MD, Director

Anne Schuchat, MD, Principal Deputy Director

Chesley L. Richards, MD, MPH, Deputy Director for Public Health Science and Surveillance

Rebecca Bunnell, PhD, MEd, Director, Office of Science

Barbara Ellis, PhD, MS, Acting Director, Office of Science Quality, Office of Science

Michael F. Iademarco, MD, MPH, Director, Center for Surveillance, Epidemiology, and Laboratory Services

MMWR Editorial and Production Staff (Serials)

Charlotte K. Kent, PhD, MPH, Editor in Chief

Christine G. Casey, MD, Editor

Mary Dott, MD, MPH, Online Editor

Terisa F. Rutledge, Managing Editor

David C. Johnson, Lead Technical Writer-Editor

Catherine B. Lansdowne, MS, Project Editor

Martha F. Boyd, Lead Visual Information Specialist

Maureen A. Leahy, Julia C. Martinroe,

Stephen R. Spriggs, Tong Yang,

Visual Information Specialists

Quang M. Doan, MBA, Phyllis H. King,

Terraye M. Starr, Moua Yang,

Information Technology Specialists

MMWR Editorial Board

Timothy F. Jones, MD, Chairman

Ileana Arias, PhD

Matthew L. Boulton, MD, MPH

Jay C. Butler, MD

Virginia A. Caine, MD

Katherine Lyon Daniel, PhD

Jonathan E. Fielding, MD, MPH, MBA

David W. Fleming, MD

William E. Halperin, MD, DrPH, MPH

Jewel Mullen, MD, MPH, MPA

Jeff Niederdeppe, PhD

Patricia Quinlisk, MD, MPH

Stephen C. Redd, MD

Patrick L. Remington, MD, MPH

Carlos Roig, MS, MA

William Schaffner, MD

Morgan Bobb Swanson, BS

CONTENTS

Introduction ............................................................................................................1

Methods

....................................................................................................................2

Risk for Exposure to Anthrax

.............................................................................3

Summary of Key Findings...................................................................................3

Recommendations for Prevention of Anthrax Among Persons with

Potential Risk for Exposure: PrEP

................................................................... 7

Recommendations for Prevention of Anthrax Among Persons with

Suspected or Known Exposure: PEP

...........................................................8

Vaccine Adverse Events Reporting and Additional Information

....... 10

Future Directions

................................................................................................ 10

References

............................................................................................................ 11

Recommendations and Reports

MMWR / December 13, 2019 / Vol. 68 / No. 4 1

US Department of Health and Human Services/Centers for Disease Control and Prevention

Use of Anthrax Vaccine in the United States: Recommendations of the

Advisory Committee on Immunization Practices, 2019

William A. Bower, MD

; Jarad Schiffer, MS

; Robert L. Atmar, MD

; Wendy A. Keitel, MD

; Arthur M. Friedlander, MD

; Lindy Liu, MPH

;

Yon Yu, PharmD

; David S. Stephens, MD

; Conrad P. Quinn, PhD

; Katherine Hendricks, MD

Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC;

Division of Bacterial Diseases,

National Center for Immunization and Respiratory Diseases, CDC;

Department of Medicine, Baylor College of Medicine, Houston, Texas;

Department of

Molecular Virology & Microbiology and Department of Medicine, Baylor College of Medicine, Houston, Texas;

U.S. Army Medical Research Institute of Infectious

Diseases, Frederick, Maryland;

Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, CDC;

Department of Medicine, Emory University, Atlanta, Georgia;

Office of Laboratory Science, CDC

Summary

This report updates the 2009 recommendations from the CDC Advisory Committee on Immunization Practices (ACIP) regarding

use of anthrax vaccine in the United States (Wright JG, Quinn CP, Shadomy S, Messonnier N. Use of anthrax vaccine in the

United States: recommendations of the Advisory Committee on Immunization Practices [ACIP)], 2009. MMWR Recomm

Rep 2010;59[No. RR-6]). The report 1) summarizes data on estimated efficacy in humans using a correlates of protection model

and safety data published since the last ACIP review, 2) provides updated guidance for use of anthrax vaccine adsorbed (AVA) for

preexposure prophylaxis (PrEP) and in conjunction with antimicrobials for postexposure prophylaxis (PEP), 3) provides updated

guidance regarding PrEP vaccination of emergency and other responders, 4) summarizes the available data on an investigational

anthrax vaccine (AV7909), and 5) discusses the use of anthrax antitoxins for PEP.

Changes from previous guidance in this report include the following: 1) a booster dose of AVA for PrEP can be given every

3 years instead of annually to persons not at high risk for exposure to Bacillus anthracis who have previously received the initial

AVA 3-dose priming and 2-dose booster series and want to maintain protection; 2) during a large-scale emergency response, AVA

for PEP can be administered using an intramuscular route if the subcutaneous route of administration poses significant materiel,

personnel, or clinical challenges that might delay or preclude vaccination; 3) recommendations on dose-sparing AVA PEP regimens

if the anthrax vaccine supply is insufficient to vaccinate all potentially exposed persons; and 4) clarification on the duration of

antimicrobial therapy when used in conjunction with vaccine for PEP.

These updated recommendations can be used by health care providers and guide emergency preparedness officials and planners

who are developing plans to provide anthrax vaccine, including preparations for a wide-area aerosol release of B. anthracis spores.

The recommendations also provide guidance on dose-sparing options, if needed, to extend the supply of vaccine to increase the

number of persons receiving PEP in a mass casualty event.

Introduction

Anthrax is an acute febrile illness caused by infection with

Bacillus anthracis. The mortality rate, even with treatment,

ranges from <2% for cutaneous anthrax (1) to 45% for

inhalation anthrax (2) and 92% for anthrax meningitis (3).

B. anthracis is a zoonotic pathogen that primarily infects sheep,

goats, cattle, and other herbivores. Humans become infected

after exposure to infected animals or contaminated animal

products or, rarely, as a complication from injection drug use

(4). B. anthracis is also a tier 1 select agent and is considered one

of the bioterrorism agents that is most likely to be used because

it is relatively easy to acquire from the natural environment,

mass produce, and disseminate as spores via aerosolization (5).

Anthrax vaccine adsorbed (AVA) (BioThrax) is licensed for

preexposure prophylaxis (PrEP) for adults aged 18–65 years

at high risk for exposure to B. anthracis (6). The dosage

approved by the U.S. Food and Drug Administration (FDA)

is 0.5 mL administered intramuscularly (IM) at 0, 1, and

6 months with boosters at 6 and 12 months after completion

of the primary series and at 12-month intervals thereafter.

AVA also is licensed for postexposure prophylaxis (PEP) in

combination with antimicrobials for adults aged 18–65 years

with suspected or known exposure to aerosolized B. anthracis

spores. The dosage approved by FDA is 0.5 mL administered

subcutaneously (SC) at 0, 2, and 4 weeks. For persons not

included in the FDA-approved indication for PEP, AVA

will be available for PEP use for children, pregnant women,

nursing mothers and older adults (i.e., ≥66 years) under

Corresponding author: William A. Bower, Division of High-

Consequence Pathogens and Pathology, National Center for Emerging

and Zoonotic Infectious Diseases, CDC. Telephone: 404-639-0376;

E-mail: [email protected]v.

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appropriate emergency use regulatory provisions. Although

data are lacking on the immune impact of mixing the IM and

SC routes of administration, as might occur when switching

from PrEP to PEP, switching between routes would be

unlikely to adversely impact immunity because both routes

provide adequate immunity.

AV7909 (AVA plus CpG 7909 adjuvant) is a second-

generation anthrax vaccine produced by Emergent BioSolutions

that is in a phase 3 trial (https://clinicaltrials.gov). The

CpG 7909 adjuvant binds to the Toll-like receptor 9 to enhance

the immune response to coadministered antigens (primarily

B. anthracis protective antigen) (7,8). The PEP schedule,

under clinical evaluation for AV7909, is 0.5 mL AVA with

0.25 mg CpG 7909 adjuvant administered IM at 0 and 2 weeks

postexposure, combined with antimicrobials.

Since the publication in 2010 of the Advisory Committee on

Immunization Practices (ACIP) recommendations for use of

anthrax vaccine in the United States (9), published studies have

1) addressed the efficacy, immunogenicity, and reactogenicity

of the recommended and alternate dose-sparing schedules of

AVA; 2) estimated AVA efficacy in humans from data on animal

efficacy and human antibody levels by using a correlates of

protection model; and 3) evaluated whether developing chronic

illnesses or having adverse pregnancy outcomes are associated

with previous AVA receipt. In addition, AV7909 phase 1 and 2

clinical trials have demonstrated the potential of AV7909 for

use as the vaccine component of PEP (PEP-Vx) (10–12).

Given these newly available data, CDC asked ACIP to

revise the recommendations for use of anthrax vaccines in

the United States. These revised recommendations address

the IM versus SC administration of AVA for PEP and the use

of reduced-schedule and half-dose AVA during public health

emergencies, shortening the duration of antimicrobials given

in conjunction with PEP-Vx, and extending the AVA PrEP

booster dose interval after the initial priming and booster

series. This report provides recommendations and guidance

regarding the use of AVA for PrEP and PEP and updates the

ACIP anthrax vaccination recommendations published in

2002 and 2010. This report also describes available data for

AV7909 because of its potential for prelicensure emergency

use during a large-scale anthrax public health emergency

if the AVA supply is inadequate. This report can be used

by health care providers to update the current practice for

providing anthrax vaccine for PrEP and PEP and can be used

by emergency preparedness partners to develop emergency

vaccine response plans in preparation for a wide-area

aerosolized release of B. anthracis spores.

Methods

During March 2017–January 2019, the ACIP Anthrax

Vaccines Work Group (AVWG), which comprises professionals

from academic medicine (internal medicine, pediatrics,

obstetrics, and infectious disease specialists), federal and state

public health entities, and medical societies, participated in

monthly telephone conferences facilitated by CDC. During

these meetings, AVWG reviewed relevant scientific evidence

and evaluated the quality of the evidence assessing the

1) immunogenicity and safety of an extended booster dose

interval for PrEP in persons not at high risk for exposure

to B. anthracis but who might have a future high risk for

exposure; 2) benefits and harms of the IM versus SC route

of administration for PEP-Vx; 3) benefits and harms of AVA

dose-sparing schedules (i.e., 2 full doses or 3 half doses) for

PEP-Vx if vaccination demands were to exceed vaccine supply

after a wide-area aerosolized release of B. anthracis spores;

4) immunogenicity and safety of AV7909, based on available

data; and 5) use of anthrax antitoxin for PEP in conjunction

with anthrax vaccine.

A scientific literature search was conducted through a

systematic review for studies involving human subjects or for

animal studies that met criteria for the Animal Rule (13,14)

that reported primary data on important health outcomes

related to AVA or AV7909 published after 2008. The previous

ACIP review summarized the data through 2008 (9). Databases

searched in February 2017 included Medline (OVID), Embase

(OVID), CAB Abstracts (OVID), Global Health (OVID),

CINAHL (Ebsco), Econlit (Ebsco), Cochrane Library, Clinical

Trials.gov, FedRip (Ebsco), the U.S. Department of Defense

(DoD) Technical Information Center, NTIS:NTRL, Scopus,

WHOLIS, and WorldCat. Search terms included anthrax

vaccine, AVA, Biothrax, Nuthrax, AV7909, CpG DNA,

CpG 7909, CpG motifs, CpG oligodeoxynucleotide, Anthim,

Anthrasil, obiltoxaximab, and raxibacumab. In addition, the

work group reviewed unpublished data from the CDC Anthrax

Vaccine Research Program, unpublished data from the vaccine

manufacturer, and results of studies from the Vaccine Analytic

Unit, which is a CDC-led collaboration with DoD and FDA

that assessed potential associations of AVA with development

of chronic conditions (15). The review of vaccine safety also

included adverse events reported to the Vaccine Adverse Event

Reporting System (VAERS) after AVA administration for

January 1, 2009, through June 30, 2017 (16). To qualify as a

candidate for inclusion in the review, a study had to present

immunogenicity or safety data on AVA, AV7909, or infectious

disease vaccines that used CpG 7909 adjuvant. Studies were

excluded if they lacked mention of either AVA or AV7909 for

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the prevention of anthrax, lacked primary data, or were outside

the time frame of interest.

Data were abstracted and summarized for immunogenicity

outcomes of interest, including seroconversion, geometric

mean concentration (GMC) of anti-protective antigen

immunoglobulin G (anti-PA IgG, determined by enzyme-

linked immunosorbent assay), geometric mean titer (GMT) of

toxin neutralization activity (TNA), effective dose 50 (ED

)

levels, and GMT of TNA neutralization factor 50 (NF

)

levels. Data also were abstracted and summarized for safety

outcomes of interest, including injection site adverse events,

systemic adverse events, and serious adverse events. Quality of

evidence was evaluated and presented in tabular format using

the Grading of Recommendations Assessment, Development

and Evaluation (GRADE) approach (17).

Evidence that had been summarized for and reviewed

by AVWG was publicly presented at the ACIP meetings

in June 2017, October 2017, February 2018, June 2018,

October 2018, and February 2019 (18). After a public

comment period, ACIP voting members at the June 2018

and February 2019 meetings unanimously approved the

proposed recommendations.

Risk for Exposure to Anthrax

The risk for exposure to aerosolized B. anthracis spores in

the United States is very low (19). Anthrax is only endemic

in a few sparsely populated areas in the western United States

(20). Certain occupations and other activities place persons at

higher risk for exposure (21). These include laboratory work

that involves bioproduction of large quantities, volumes, or

high concentrations of B. anthracis spores and activities with

a high potential for exposure to aerosolized B. anthracis spores,

such as military deployment to areas designated by DoD as

posing a high risk for anthrax exposure and emergency response

activities after release of B. anthracis spores (9).

The possibility exists of an intentional wide-area aerosolized

release of B. anthracis spores over a densely populated area in the

United States. In 2001, letters containing B. anthracis spores

sent through the U.S. Postal Service led to 22 cases of anthrax,

five of which were fatal (22). In addition, certain countries and

terrorist groups have explored the use of anthrax as a bioweapon

(23–25). An aerosolized release of B. anthracis spores over

densely populated areas could become a mass-casualty incident

(26). However, previously developed, publicly available

clinical recommendations only addressed clinical management

using conventional standards of care (27). To prepare for the

possibility of an anthrax mass-casualty incident, when the

number of patients is likely to exceed the ability of the health

care infrastructure to provide conventional standards of care

and supplies might not meet demand, the U.S. government

has stockpiled equipment and therapeutics (i.e., medical

countermeasures) for anthrax prevention and treatment

and provided recommendations for their use (28). The U.S.

government’s Strategic National Stockpile stores anthrax

vaccine to be used with antimicrobials for PEP of persons with

known or potential exposure to B. anthracis spores, as well

as therapeutics and supplies for anthrax treatment. Animal

models have shown that although 5–30 days of antimicrobials

might be insufficient to prevent anthrax after single exposures

or reexposures to B. anthracis spores, the addition of vaccine

substantially enhances efficacy (29–31). In the event of a

large-scale release of B. anthracis spores, the Strategic National

Stockpile will distribute medical countermeasures to affected

states, and state and local public health agencies will then

dispense antimicrobials to and vaccinate numerous at-risk

persons. Antimicrobials are given long enough (up to 60 days)

to prevent infection until the vaccine can elicit a protective

immune response (29).

Summary of Key Findings

Anthrax Vaccine Adsorbed

Because human efficacy studies of inhalation anthrax are

unethical, the effectiveness of AVA for PEP cannot be directly

assessed in humans. For this situation, FDA allows the use

of the Animal Rule, a set of regulations that allow approval

of products critical for the protection of public health and

national security based on efficacy data only in animals

combined with immunogenicity and safety data in animals

and humans (32). Under the Animal Rule, AVA vaccine-

induced antibody levels were extrapolated from vaccine efficacy

studies conducted in animals to predict vaccine effectiveness

in humans (33). Statistical modeling was used to establish

the relation between survival of AVA-vaccinated animals

challenged with B. anthracis spores and their antibody levels

at the time of infectious challenge. This relation was applied

to postvaccination antibody levels in humans to estimate the

probability of human survival at selected time points (34).

Route of Administration and Immunogenicity of

AVA for PEP

The SC route of administration of AVA is preferred in

adults because SC administration results in higher antibody

concentrations by week 4 than the IM route: males SC,

40.8

µg/mL (95% confidence interval [CI]: 34.0–49.1);

males IM, 26.3

µg/mL (95% CI: 21.9–31.2); females SC,

60.2

µg/mL, (95% CI: 50.1–72.3), females IM, 36.0 µg/ml

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(95% CI: 30.0–43.1 (35). Using these antibody concentrations,

survival estimates based on the correlates of protection model

are 3.8% higher for the SC route (92.4%) than the IM route

(88.6%) of administration at week 4 (36). However, by week 9,

the antibody concentrations and predicted survival from the

IM route (95.6%) and SC route (96.1%) are no longer

significantly different (35).

In a wide-area aerosolized release of B. anthracis spores over

a densely populated area, potentially hundreds of thousands of

exposed persons might require PEP-Vx to prevent inhalation

anthrax. In such a situation, rapid and efficient administration

of vaccine to large numbers of persons would be a key

component of the public health emergency response. Health

care providers typically have more experience administering

vaccines by the IM route than the SC route. In addition,

during a conference call with state and local jurisdictions, many

public health officials indicated that they plan to use just-in-

time training for responding vaccinators during a wide-area

aerosolized release of B. anthracis spores. Officials also stated

during this call that training vaccinators to use the IM route

was the easiest (State and local public health preparedness

officials, personal communication, 2018). In addition, a study

comparing the IM and SC route for AVA administration found

significantly less reactogenicity (less injection site warmth,

itching, erythema, induration, swelling, and nodule formation)

with the IM route than with the SC route at 0, 2, and 4 weeks.

In this same study, only two adverse events were more common

among IM AVA recipients than SC AVA recipients: limitation

of arm motion and generalized myalgia (35). Because the

preponderance of injection site adverse events was associated

with the SC route, concern has been raised that using this

route might decrease the likelihood of patients completing the

second and third doses of AVA.

Dose-Sparing Strategies for PEP-Vx

A wide-area aerosolized release of B. anthracis spores over

a densely populated area could potentially require PEP-Vx

of more persons than could be vaccinated with the available

supply of AVA in the Strategic National Stockpile if AVA were

to be administered according to the licensed regimen (0.5 mL

at 0, 2, and 4 weeks) for the PEP-Vx indication. If demand

were to exceed the supply, alternative AVA dose-sparing

regimens might be needed to provide PEP-Vx to all persons

with suspected or known exposure to aerosolized B. anthracis

spores. To address this problem, studies were reviewed that

estimated survival with AVA administered according to the

licensed PEP-Vx schedule (3 full [0.5-ml] doses at 0, 2, and

4 weeks) versus alternate dose-sparing schedules (i.e., 2 full

doses at 0 and 2 weeks, 2 full doses at 0 and 4 weeks, and

3 half [0.25-ml] doses at 0, 2, and 4 weeks) (Figure). The

three groups who received an AVA dose at week 2 had higher

antibody concentrations at week 4 than the one group who

FIGURE. Group geometric means for anti-protective antigen immunoglobulin G enzyme-linked immunosorbent assay over time after

administration of anthrax vaccine adsorbed*

0.1

100

1,000

0 2 4 6 8 10

Weeks since rst dose

0, 2 Full dose

0, 4 Full dose

0, 2, 4 Full dose

0, 2, 4 Half dose

PA80

Anti-PA IgG (μg/mL)

Abbreviations: AVA = anthrax vaccine adsorbed; IgG = immunoglobulin G; PA = protective antigen.

* 0, 2 Full dose = 0.5 mL AVA administered at 0 and 2 weeks; 0, 4 Full dose = 0.5 mL AVA administered at 0 and 4 weeks; 0, 2, 4 Full dose = 0.5 mL AVA administered at

0, 2, and 4 weeks; 0, 2, 4 Half dose = 0.25 mL AVA administered at 0, 2, and 4 weeks; PA80 = 80% predicted protection level.

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did not. The dose-sparing schedule of 2 full doses administered

4 weeks apart produced the highest antibody concentrations

from week 6 onward after the first dose. The 3 full-dose

regimen produced higher antibody concentrations than when

the vaccine was administered as 3 half doses at all measured

time points after week 1. The peak response was measured

2 weeks after the last dose for the licensed and dose-sparing

PEP-Vx schedules and was estimated to be highly protective

by the correlates of protection model (37). The predicted

survival was estimated to be 97.4% (95% CI: 85.1–100) for the

licensed schedule, 95.8% (95% CI: 92.2–100) for the full dose

administered at 0 and 2 weeks, 98.1% (95% CI: 86.9–100)

for the full dose administered at 0 and 4 weeks, and 96.1%

(95% CI: 83.7–100) for the 3 half doses administered at 0, 2,

and 4 weeks (Table 1). All dosing PEP-Vx schedules maintain

a high level of predicted survival through week 9 (36,38).

Duration of Antimicrobial Administration in

Combination with Vaccine

Since 2000, FDA has approved several oral antimicrobials

(ciprofloxacin in 2000, penicillin G in 2001, doxycycline in

2001, and levofloxacin in 2004) for antimicrobial postexposure

prophylaxis (PEP-Abx) of anthrax. Each PEP-Abx regimen

should be administered for 60 days when not used in

combination with vaccine. However, studies of nonhuman

primates have demonstrated that spores can persist in the

lungs many days after inhalation exposure (up to 100 days

in one animal study) and that anthrax can develop after

discontinuation of PEP-Abx (29,30). Because of the possibility

of delayed infection from persistent spores, recommendations

for PEP require use of AVA in conjunction with antimicrobial

drugs. With this strategy, the antimicrobials protect against

germinating spores until the vaccine can elicit a protective

immune response.

Using the limited data available at the time, in 2015, FDA

licensed a 3-dose regimen of AVA to be given in conjunction

with recommended antimicrobials for PEP for persons

potentially exposed to aerosolized B. anthracis spores (39).

Newer data from a human clinical trial with AVA demonstrate

that, with concurrent receipt of AVA, the duration of

antimicrobial use can be shortened from the recommended

60 days (38). In the trial, persons were given one of four

PEP-Vx regimens: the licensed 3-dose schedule, a dose-sparing

schedule with 2 full doses at 0 and 2 weeks, a dose-sparing

schedule with 2 full doses at 0 and 4 weeks, or a dose-sparing

schedule with 3 half doses at 0, 2, and 4 weeks. Antibody

levels predicted to be protective in humans were extrapolated

from a matched nonhuman primate nonclinical trial in which

48 nonhuman primates were given 2 doses of AVA at 0 and

2 weeks and challenged with a 200 LD

dose of B. anthracis

spores at week 4. Protection provided by anti-PA IgG was

modeled using logistic regression of the measured prechallenge

antibody levels at week 4 in nonhuman primates versus survival

of challenge (36). The nonhuman primate prediction curve

was then applied to the human antibody levels to predict

protection in humans (38). The estimated peak protection both

for licensed and dose-sparing AVA PEP-Vx regimens occurred

2 weeks after the last AVA dose was given. All regimens are

estimated to be highly protective; protection is maintained

through day 60, when the antimicrobial component of PEP

is recommended to end (Table 1).

Safety

Since 2008, the vast majority of AVA vaccinations

(approximately 8 million doses administered to approximately

1.9 million persons) have been administered by DoD as PrEP

to its service members. The PrEP route of administration

was SC until FDA approved changing the PrEP route of

administration to IM in December 2008. As defined by the

TABLE 1. Anthrax vaccine adsorbed postexposure prophylaxis schedules and predicted human survival*

Time from rst dose

of PEP-Vx

Predicted human survival by PEP-Vx schedule

Licensed vaccination regimen Alternate dose-sparing schedules

Full dose at 0, 2, and 4 wks Full dose

†

at 0 and 2 wks Full dose at 0 and 4 wks Half dose

at 0, 2, and 4 wks

% (95% CI) % (95% CI) % (95% CI) % (95% CI)

Week 4 95.8 (92.2–100) 95.8 (82.6–100) 72.6

(58.2–92.9) 91.1 (78.2–98.7)

Week 6 97.4 (85.1–100) 95.5 (81.7–100) 98.1 (86.9–100) 96.1 (83.7–100)

Week 9 96.4 (83.1–100) 93.3 (78.9–100) 97.0 (84.4–100) 94.2 (80.8–100)

Source: Data from Stark GV, Sivko GS, VanRaden M, et al. Cross-species prediction of human survival probabilities for accelerated anthrax vaccine adsorbed (AVA)

regimens and the potential for vaccine and antibiotic dose sparing. Vaccine 2016;34:6512–7.

Abbreviations: AVA = anthrax vaccine adsorbed; CI=confidence interval; PEP-Vx = AVA postexposure prophylaxis.

* Based on survival data from nonhuman primates that received AVA at weeks 0 and 2 and were challenged with a target dose of 200 LD

aerosolized Bacillus anthracis

spores at week 4.

†

0.5 mL of AVA.

0.25 mL of AVA.

At 4 weeks before the second dose of vaccine.

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U.S. Code of Federal Regulations, an event is classified as

serious if one or more of the following conditions is reported:

death, a life-threatening illness, hospitalization or prolongation

of existing hospitalization, permanent disability, or a congenital

anomaly or birth defect (40).

From January 1, 2009, through

June 30, 2017, a total of 2,439 AVA-related adverse events

were reported to VAERS (16); 329 (13.5%) of these were

considered serious.

During the same period, the 10 most common reported

adverse events were coded as headache (14.7%), injection

site erythema (13.6%), pain (12.6%), fever (11.6%), fatigue

(11.5%), arthralgia (11.2%), erythema (11.2%), injection site

pain (9.9%), injection site swelling (9.8%), and rash (9.4%)

on the basis of coding terms from the Medical Dictionary for

Regulatory Activities. VAERS has numerous strengths, such as

broad national scope and early detection of possible new, rare,

or unusual patterns of adverse events. However, VAERS is a

spontaneous reporting system that has important limitations,

including underreporting, inconsistent data quality and report

completeness, and lack of an unexposed comparison group.

Therefore, the data generally cannot be used to assess whether

a vaccine caused an adverse event (16).

Nine studies, including clinical vaccine trials and observational

studies (10,12,35,37,41–45), also assessed serious adverse

events after administration of AVA, AV7909, or both in

human subjects. Serious adverse events were reported in three

studies (12,35,43); however, only in the Anthrax Vaccine

Review Program study (35) were the serious adverse events

considered possibly related to AVA. In this study, 231 adverse

events were identified in recipients of approximately 8,300

doses of AVA. Six serious adverse events, none of which was

fatal, were considered to be possibly related to the vaccine,

including ductal carcinoma of the breast, generalized allergic

reaction, new onset bilateral arthralgia of the metacarpal

joints associated with positive antinuclear antibody (ANA),

bilateral pseudotumor cerebri, supraspinatous tendon tear, and

new onset of generalized seizures associated with aqueductal

stenosis (35).

In studies from the Vaccine Analytic Unit and other groups

published since 2010, no association was found between AVA

receipt and the following chronic health conditions: reduction

in health-related quality of life measures (46), multisystem

illness (47), long-term disabilities (48,49), type 1 diabetes (50),

atrial fibrillation (51), and diffuse connective tissue diseases

(52). In one case-control study, an association was identified

between AVA receipt and new-onset rheumatoid arthritis if a

look-back period of 3 months was used (odds ratio [OR]: 3.93;

95% CI:1.08–14.27). However, no association between AVA

and rheumatoid arthritis was identified if a longer look-back

period of 3 years was used (OR: 1.03; 95% CI:0.48–2.19)

(52), suggesting that AVA exposure might trigger onset of

rheumatoid arthritis in persons who would eventually have

developed rheumatoid arthritis later in life.

Although AVA is not intended for use during pregnancy,

DoD maintains a registry of women inadvertently vaccinated

while pregnant. Studies of adverse outcomes and a cohort study

of birth defects using this registry did not detect any increased

rates of adverse fetal or infant outcomes among women who

received AVA during their first trimester compared with receipt

at other time points or no receipt of AVA (53,54). Finally,

because no safety data are available for AVA use in adolescents, a

presidential ethics commission proposed comparing AVA safety

data for the group aged 18–20 years (the youngest group) and

the group aged 21–29 years. If no significant safety difference

could be found between the two age groups, then evaluations

could proceed in successively younger adolescents. In a study

following these suggested methods, AVA was deemed safe

in adults aged 18–20 years (44); no additional studies have

been conducted in younger age groups. AVWG reviewed the

VAERS reports and the published literature and presented

their findings to the ACIP committee. On the basis of these

data, the committee concluded that no clinically significant

safety concerns have been identified related to receipt of AVA

since 2010 (9).

AV7909

AV7909 is an investigational second-generation anthrax

vaccine that is under development for PEP of inhalation

anthrax in conjunction with appropriate antimicrobials.

AV7909 consists of the licensed AVA combined with a

novel adjuvant, CpG 7909, a synthetic immunostimulatory

oligodeoxynucleotide. CpG 7909 is a Toll-like receptor 9

agonist that has been demonstrated to augment Th1 responses

in humans and enhance innate and adaptive immunity (7,8)

AV7909 is intended to be added to the Strategic National

Stockpile. CDC has submitted a pre–Emergency Use

Authorization (EUA) request to FDA to allow potential

emergency use of AV7909, in conjunction with appropriate

PEP-Abx, for PEP of inhalation anthrax when the supply of

the currently licensed AVA is inadequate. EUA is an authority

given to the FDA commissioner to legally permit the use of

an unapproved medical product or unapproved use of an

approved medical product (55). Under the proposed EUA,

AV7909 would be administered by the IM route as a 2-dose

series 2 weeks apart in conjunction with PEP-Abx for adults

aged 18–65 years. Pregnant or nursing mothers, older adults

(aged ≥66 years), and children (aged <18 years) should receive

AVA until data to adequately support AV7909 use in these

additional populations under EUA become available.

Recommendations and Reports

MMWR / December 13, 2019 / Vol. 68 / No. 4 7

US Department of Health and Human Services/Centers for Disease Control and Prevention

Available data indicate that AV7909 might provide the

following advantages over AVA:

• Two IM doses of AV7909 administered 2 weeks apart

might provide protective immunity 1–2 weeks sooner than

the licensed 3-dose PEP-Vx regimen of AVA.

• Compared with the licensed 3-dose AVA PEP-Vx schedule,

the 2-dose schedule of AV7909 PEP provides an operational

advantage in a large-scale, mass vaccination response.

• Adherence might be better because more persons are likely

to complete the 2-dose AV7909 PEP series than the 3-dose

AVA PEP series.

Immunogenicity

The initial phase 1 clinical trial assessed immunogenicity

of AVA alone and AVA plus CpG 7909 in 69 healthy adults

aged 18–45 years (12). Vaccinations were administered IM on

weeks 0, 2 (±1 day), and 4 (±2 days). The CpG group received

AVA plus 1 mg of CpG 7909. The results showed that the

peak GMT of TNA for the AV7909 group was 8.8-fold higher

than that observed for the AVA-alone group; antibody peaked

at week 6 in both arms. By week 3, GMT in the CpG group

exceeded the peak GMT in the AVA group (reached at week 6).

The TNA results paralleled those observed with anti-PA IgG,

and in both assays the differences between AVA and AV7909

were statistically significant. Analysis of the phase 2 TNA

threshold of protection data for AV7909 revealed that addition

of the CpG 7909 adjuvant to AVA improved the kinetics and

magnitude of the immune response (56). A 2-dose AV7909

regimen with 0.25 mg of CpG 7909 administered IM resulted

in a similar serological response at week 9 compared with a

3-dose AVA regimen administered IM and achieved a peak

response by week 4 versus week 6 for AVA.

Safety

Adverse events were assessed in three clinical trials available

at the time of this review, including a total of 241 subjects who

were administered at least 1 dose of AVA plus CpG 7909 in

varying dose combinations (10,12,45). The most common

adverse events, reported in ≥20% of persons receiving AV7909

across these clinical trials, were injection site reactions (e.g.,

mild to moderate pain, tenderness, and arm motion limitation);

these typically resolved within 48 hours of administration.

Systemic reactogenicity manifested primarily as mild to

moderate fatigue, muscle ache, and headache. No deaths or

serious adverse events assessed as being causally associated have

been reported in AV7909 clinical studies.

In healthy adults aged 18–50 years who received

CpG 7909-adjuvanted experimental vaccines for malaria and

hepatitis B in the 0.25-mg dose that is combined with AVA

in AV7909 (57,58), local and systemic reactions were similar

to those observed in the groups who received malaria and

hepatitis B vaccines without CpG 7909, and the proportion

of subjects who dropped out because of adverse events

did not differ between treatment and control groups (58).

Reasons for discontinuation included rash, positive ANA,

generalized pruritus, urticaria, and fever. These clinical trial

reports suggested that these adverse events might be a result of

activation of proinflammatory innate immune responses at the

injection site. Theoretically, CpG 7909 could trigger the onset

of autoimmune disease, possibly as a result of nonspecific T or B

lymphocyte activation. Some studies reported mild to moderate

increases in anti–double-stranded DNA antibody, rheumatoid

factor, or positive ANA results. However, these increases in

immune markers were typically transient. No adverse events

suggesting autoimmune disease have been reported in the

reviewed published data on CpG 7909-adjuvanted infectious

disease vaccine trials (57–61). No safety data are available for

CpG 7909-adjuvanted vaccines, including AV7909 among

special populations (e.g., children, persons aged >65 years,

and pregnant women).

Recommendations for Prevention of

Anthrax Among Persons with

Potential Risk for Exposure: PrEP

ACIP previously recommended AVA PrEP for prevention of

anthrax in persons at high risk for exposure to B. anthracis (e.g.,

members of the U.S. military deployed to areas designated by

DoD as high risk for exposure, laboratory workers who work

with high concentrations of B. anthracis, and persons such

as farmers, veterinarians, and livestock handlers who might

handle infected animals or contaminated animal products) (9).

In this report, ACIP recommends that a booster dose of AVA

PrEP be given every 3 years to persons who are not at high risk

for exposure to B. anthracis who have previously completed

the 3-dose primary and the initial 2-dose boosters AVA series

and want to maintain protection.

The PrEP schedule for persons at high risk for exposure

to B. anthracis is AVA administered IM as a priming series at

0, 1, and 6 months, with booster doses at 12 and 18 months and

annually thereafter. If the vaccination schedule is interrupted,

the series does not need to be restarted. After the priming series

is completed, persons can work in high-risk areas of exposure

with appropriate personal protective equipment and biosafety

measures. Documentation of seroconversion is not required. If

biosafety or respiratory protection measures are breached and

exposure to aerosolized B. anthracis spores might have occurred,

a 30-day course of PEP-Abx is recommended, regardless of

whether PrEP has been fully or partially completed.

Recommendations and Reports

8 MMWR / December 13, 2019 / Vol. 68 / No. 4

US Department of Health and Human Services/Centers for Disease Control and Prevention

Because of the lack of a quantifiable risk, emergency and

other responders are not recommended to receive routine

PrEP vaccination. However, emergency responders, because

of the requirements of their occupation, might be exposed

to aerosolized B. anthracis spores and thus may opt to receive

the vaccine on a voluntary basis. For persons who are not

currently at high risk for exposure to B. anthracis but who

might be at high risk in the future (e.g., persons involved in

emergency response activities), published data (35) support

a booster dose interval of >1 year. Thus, a booster dose of

AVA can be given every 3 years to persons not at high risk for

exposure to B. anthracis who have previously received the initial

AVA priming and booster series and who want to maintain

protection. After completing the initial 3-dose priming

and booster series, persons who have not received a booster

dose in the last 12 months and need to enter an area where

B. anthracis is suspected to be present in the environment or

be in use should be given an IM booster dose and then either

wait 2 weeks to enter the high-risk area or, if required to enter

immediately, take PEP-Abx for 2 weeks. While in a high-risk

area, a booster dose should be given within 1 year of the last

booster dose.

Persons who are exposed to aerosolized B. anthracis spores

but have not completed the initial priming and booster series

for AVA should receive additional AVA doses and PEP-Abx.

The number of vaccine doses and duration of PEP-Abx will

vary in a manner commensurate with the number of previously

received doses (Table 2).

Recommendations for Prevention of

Anthrax Among Persons with

Suspected or Known Exposure: PEP

ACIP recommends AVA for use in adults aged 18–65 years

to be given in conjunction with a course of antimicrobials

(Table 3) to prevent infection after suspected or known

exposure to aerosolized B. anthracis spores. Antimicrobial

duration details are provided (Table 4). The vaccine is given

at a dose of 0.5 mL SC at 0, 2, and 4 weeks postexposure,

unless the emergency response requires a change to the IM

route or use of dose-sparing regimens. If the PEP-Vx schedule

is interrupted, the series does not need to be restarted. Instead,

subsequent doses should be administered as soon as possible,

and the series should be finished.

Route of Administration

ACIP recommends the SC route of administration

rather than the IM route for PEP because higher antibody

concentrations are achieved by 4 weeks after AVA vaccination.

However, during a large-scale emergency response, AVA for

PEP can be administered using an IM route if the SC route

of administration poses significant materiel, personnel, or

clinical challenges that might delay or preclude vaccination. In

addition, persons who experienced adverse events from AVA

that was administered SC may elect to receive subsequent

vaccine doses IM after consultation with a health care provider.

Doses of AVA inadvertently administered by the IM route

rather than the SC route do not need to be repeated by the

SC route.

Dose-Sparing PEP Regimens

ACIP recommends use of dose-sparing PEP regimens if the

anthrax vaccine supply is insufficient to vaccinate all potentially

exposed persons. The 2 full-dose strategy will expand the

existing vaccine supply by 50%, and the 3 half-dose strategy

will expand the supply by 100%. Immediately after a wide-area

aerosolized release of B. anthracis spores, the preferred dose-

sparing PEP regimen might not be apparent until the size of

the event is determined. All dose-sparing PEP-Vx regimens

are estimated to provide high levels of protection 2 weeks after

the last dose (Table 5). Existing data indicated that 2 doses

administered 2 weeks apart or 4 weeks apart are effective;

therefore, the 2-dose schedule should be ≥2 weeks apart and

≤4 weeks apart, recognizing that full protection is not achieved

until 2 weeks after the second dose (37).

Antimicrobial Duration in Conjunction

with FDA-Licensed or Dose-Sparing PEP

Regimens of AVA

ACIP recommends that in immunocompetent adults (e.g.,

healthy, nonpregnant adults aged 18–65 years), PEP-Abx

both for the licensed and dose-sparing PEP-Vx regimens can

be discontinued 42 days after initiation of vaccine if AVA is

administered on schedule for both the licensed and dose-

sparing PEP-Vx regimens (Table 4). If the AVA series cannot

be completed, then antimicrobial therapy should continue

for 60 days. However, the second dose of AVA is critical for

producing high antibody concentrations. To account for

delays in initial vaccination that might occur because of the

emergency situation, antimicrobial administration should be

initiated as soon as possible and continued for 42 days after

the first dose or 2 weeks after the last dose of the vaccine series,

whichever comes last. No data on humans are available to

suggest that PEP-Abx should be given for >60 days, which is

the recommended duration for PEP-Abx when given without

Recommendations and Reports

MMWR / December 13, 2019 / Vol. 68 / No. 4 9

US Department of Health and Human Services/Centers for Disease Control and Prevention

TABLE 2. Transition from preexposure prophylaxis* schedule to postexposure prophylaxis schedule for persons who have not completed a

priming and initial booster series

†

and must immediately enter an area that poses a high risk

for Bacillus anthracis exposure

PrEP doses Interval since last dose

PEP

PEP-Vx PEP-Abx

0 — Dose 1 (week 0) Administer until 42 days after first dose of AVA or 14 days after last dose, whichever

occurs later.

Dose 2 (week 2)

Dose 3 (week 4)

1 — Dose 2 (week 0) Administer until 28 days after second dose of AVA or 14 days after the last dose,

whichever occurs later.

Dose 3 (week 2)

2 — Dose 3 (week 0) Administer until 14 days after last dose.

3, 4 >6 mos Booster dose Administer until 14 days after booster dose.

3, 4 ≤6 mos No booster No antimicrobials needed

Abbreviations: AVA = anthrax vaccine adsorbed; PEP = postexposure prophylaxis; PEP-Abx = antimicrobial PEP; PEP-Vx = AVA PEP; PrEP = preexposure prophylaxis.

* No data are available on the effect on the immune response for starting PrEP by the intramuscular route and switching to the subcutaneous route to join the PEP

schedule; however, no evidence suggests that the immune response would be adversely affected by mixing the routes of administration.

†

Priming doses at 0, 1, and 6 mos, with booster doses at 12 and 18 mos.

The licensed booster schedule for high-risk exposure applies while in the high-risk area.

If the AVA series cannot be completed, then antimicrobial therapy should continue for 60 days.

TABLE 3. Oral antimicrobial dosages for use in adults in conjunction

with anthrax vaccine adsorbed for postexposure prophylaxis

Strain Drug and dosage*

For all strains, regardless of

penicillin susceptibility or if

susceptibility is unknown

Ciprofloxacin,

†

500 mg every 12 hrs

Doxycycline,

†

100 mg every 12 hrs

Levofloxacin, 750 mg every 24 hrs

Moxifloxacin,

400 mg every 24 hrs

Clindamycin,

600 mg every 8 hrs

Alternatives for penicillin-

susceptible strains

Amoxicillin,

1,000 mg every 8 hrs

Penicillin VK,

500 mg every 6 hrs

Abbreviations: FDA = Food and Drug Administration; PEP-Abx = antimicrobial

postexposure prophylaxis.

* Any one of these drug regimens.

†

First-line drugs; alternative drugs are listed in order of preference for PEP-Abx

for patients who cannot take first-line treatment or if first-line PEP-Abx is

unavailable.

Not FDA approved for PEP-Abx of inhalation anthrax.

TABLE 4. Antimicrobial duration when used in conjunction with Food

and Drug Administration–licensed or dose-sparing postexposure

prophylaxis regimens of anthrax vaccine adsorbed*

Population with suspected or

known exposure

Duration of antimicrobial

regimen

Immunocompetent adults aged 18–65 yrs 42 days when initiated

concurrently with first dose of

AVA or for 14 days after last

AVA dose, whichever is later

(not to exceed 60 days)

Adults aged 18–65 yrs with

immunocompromising conditions

(e.g., cancer or HIV infection) or receiving

immunosuppressive therapy (e.g.,

high-dose corticosteroids for >2 wks

or radiation therapy)

†

60 days

All older adults (>65 yrs) 60 days

All pregnant women and nursing mothers 60 days

All children (≤17 yrs) 60 days

Abbreviation: AVA = anthrax vaccine adsorbed.

* If the AVA series cannot be completed, then antimicrobial therapy should

continue for 60 days.

†

Source: Löbermann M, Boršo D, Hilgendorf I, Fritzsche C, Zettl UK, Reisinger

EC. Immunization in the adult immunocompromised host. Autoimmun Rev

2012;11:212–8.

TABLE 5. Postexposure prophylaxis with anthrax vaccine adsorbed

dose-sparing regimens

Dose Route of administration Dosing schedule

0.5 mL (full dose) SC or IM* 2 doses: 0 and 2–4 wks

0.25 mL (half dose) SC or IM* 3 doses: 0, 2, and 4 wks

Abbreviations: IM = intramuscular; SC = subcutaneous.

* Can be administered IM if the SC route of administration poses significant materiel,

personnel, or clinical challenges that might delay or preclude vaccination.

vaccine. Thus, PEP-Abx should not be given for >60 days,

regardless of the timing of last vaccine dose.

The shortening of PEP-Abx duration from 60 days to 42 days,

or 2 weeks after the last dose of vaccine, applies to healthy

adults aged 18–65 years. Persons with immunocompromising

conditions that might interfere with their ability to develop an

adequate immune response or populations for whom data on

immune response to AVA are lacking (e.g., children, pregnant

women, and adults aged ≥65 years) should continue to receive

PEP-Abx for 60 days concurrently with AVA.

Potential Emergency Use of AV7909

Because of supply concerns and the investigational status

of AV7909, AVA should be prioritized over AV7909 for

PEP-Vx of potential exposure to aerosolized B. anthracis

spores. However, the limited amount of phase 2 safety and

immunogenicity data indicate that AV7909 appears to be

safe and effective. The benefits of an effective vaccine that

can prevent anthrax outweigh the known potential risks for

adverse events in persons potentially exposed to aerosolized

B. anthracis spores. Therefore, if supplies of AVA are exhausted

or unavailable, AV7909 is an option for PEP of persons exposed

to aerosolized B. anthracis spores under an EUA granted by

FDA. As with AVA, antimicrobials (Tables 3 and 4) should

be taken in conjunction with AV7909. Additional AV7909

Recommendations and Reports

10 MMWR / December 13, 2019 / Vol. 68 / No. 4

US Department of Health and Human Services/Centers for Disease Control and Prevention

data on safety, immunogenicity, and biocompatibility with

antimicrobials will be reviewed by ACIP as they become

available, and recommendations on potential preferential use

will be updated as needed.

No data are available on the immunogenicity or safety of

AV7909 for children or other special populations. However,

a phase 2 clinical trial is being conducted to assess the safety

and immunogenicity of AVA and AV7909 in adults aged

>65 years compared with adults aged 18–50 years (62). In

the absence of such data, AVWG considered it reasonable to

anticipate that risks and benefits of PEP-Vx for children or

special populations would be similar to those for the general

adult population. Therefore, if AVA is not available, emergency

use of AV7909 under an appropriate regulatory mechanism

should be considered for all populations with known or

potential exposure to aerosolized B. anthracis spores. Should

an anthrax exposure event occur that necessitates AV7909 use

while it remains under development and is not yet licensed,

ACIP will convene an emergency meeting to review available

data for specific recommendations on AV7909 emergency use.

No studies have been conducted on the interchangeability

of AVA and AV7909. When feasible, doses of the same vaccine

type should be used to complete a series. However, vaccination

should not be deferred because the previously used vaccine

type is unavailable. When a vaccine series uses a combination

of AVA and AV7909, 3 total doses of anthrax vaccine should

be administered and used in conjunction with appropriate

antimicrobials (Tables 3 and 5).

Antitoxin Use for PEP

Three licensed anthrax antitoxins are available from the

Strategic National Stockpile: anthrax immune globulin

intravenous (AIGIV) (63), obiltoxaximab (Anthim) (64), and

raxibacumab (ABthrax) (65). AIGIV is a polyclonal antibody,

whereas obiltoxaximab and raxibacumab are both monoclonal

antibodies. All work by binding to protective antigen, which

blocks movement of toxins into cells and therefore the effects

of toxins within the cells. All three antitoxins are indicated

in all adults and children for the treatment of inhalation

anthrax due to B. anthracis, in combination with appropriate

antimicrobial drugs.

Obiltoxaximab and raxibacumab also have an indication

for PEP of inhalation anthrax due to B. anthracis when

alternative therapies are not available or are not appropriate.

In these situations, obiltoxaximab or raxibacumab may be

considered to help prevent inhalation anthrax. The predicted

effectiveness of both antitoxins for this indication is based

solely on efficacy studies conducted in animal models of

inhalation anthrax (66,67).

Data indicate that raxibacumab can be coadministered

with AVA for PEP without affecting vaccine immunogenicity

(68). No data are available to assess whether obiltoxaximab

coadministered with AVA impairs vaccine immunogenicity.

AIGIV does not have a PEP indication because coadministration

of AIGIV and AVA in a rabbit model has been shown to

significantly reduce the development of an immune response

to AVA (68).

Vaccine Adverse Events Reporting

and Additional Information

Surveillance for serious adverse events is important for

all antimicrobials, biologics, and vaccines. All clinically

significant adverse events after receipt of antimicrobials or

anthrax antitoxin for PEP or treatment of anthrax should be

reported to the MedWatch Program (https://www.fda.gov/

safety/medwatch-fda-safety-information-and-adverse-event-

reporting-program or 888-463-6332). All clinically significant

adverse events after receipt of either AVA or AV7909 should be

reported to VAERS (https://vaers.hhs.gov or 800–822–7967).

Additional information about anthrax and anthrax vaccines is

available at https://www.cdc.gov/anthrax.

Future Directions

Research priorities for future studies on anthrax vaccines

should include assessment of immunogenicity and safety in

special populations, such as children, older adults, and pregnant

and nursing mothers; additional evaluations of the dose-sparing

schedules; evaluation of the interchangeability of AVA and

AV7909; determination of the optimal booster schedule to

provide long-term protection after receiving the PEP vaccine

schedule; testing of the stability of AVA and AV7909 outside

the cold chain; assessment of whether coadministration of

obiltoxaximab with AVA impairs vaccine immunogenicity;

and the optimal duration of antimicrobial use in postexposure

settings. Studies are planned to evaluate the effect of longer

intervals between PrEP boosters on vaccine responses. On

approval of AV7909 as a licensed vaccine, the additional data

leading to the licensure of AV7909 will be reviewed by ACIP,

and recommendations will be updated as needed.

Recommendations and Reports

MMWR / December 13, 2019 / Vol. 68 / No. 4 11

US Department of Health and Human Services/Centers for Disease Control and Prevention

Acknowledgments

Marissa Persons, Modupe Osinubi, Division of High-Consequence

Pathogens and Pathology, National Center for Emerging and Zoonotic

Infectious Diseases, CDC; Amanda Cohn, Jessica MacNeil, Office

of the Director, National Center for Immunization and Respiratory

Diseases, CDC. Advisory Committee on Immunization Practices

(ACIP) member roster for March 2017–January 2019 is available at

https://www.cdc.gov/vaccines/acip/committee/members.html.

Conflicts of Interest

All authors have completed and submitted the International Com-

mittee of Medical Journal Editors form for disclosure of potential

conicts of interest. No potential conicts of interest were disclosed.

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MMWR / December 13, 2019 / Vol. 68 / No. 4 13

US Department of Health and Human Services/Centers for Disease Control and Prevention

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Recommendations and Reports

14 MMWR / December 13, 2019 / Vol. 68 / No. 4

US Department of Health and Human Services/Centers for Disease Control and Prevention

Advisory Committee on Immunization Practices

Membership as of February 27, 2019

Chair: José R. Romero, MD, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, Arkansas.

Executive Secretary: Amanda Cohn, MD, National Center for Immunization and Respiratory Diseases, CDC, Atlanta, Georgia.

Members: Robert L. Atmar, MD, Baylor College of Medicine, Houston, Texas; Kevin A. Ault, MD, University of Kansas Medical Center, Kansas City, Kansas;

Henry Bernstein, DO, Zucker School of Medicine at Hofstra/Northwell Cohen Childrens’ Medical Center, New Hyde Park, New York; Echezona Ezeanolue,

MD, University of Nevada, Las Vegas, Nevada; Sharon E. Frey, MD, Saint Louis University Medical School, Saint Louis, Missouri; Stefan Gravenstein, MD,

Providence Veterans Administration Hospital, Providence, Rhode Island; Paul Hunter, MD, City of Milwaukee Health Department, Milwaukee, Wisconsin;

Grace M. Lee, MD, Lucile Packard Children’s Hospital, Stanford University School of Medicine, Stanford, California; Veronica V. McNally, JD, Fanny

Strong Foundation, West Bloomfield, Michigan; Kelly Moore, MD, Vanderbilt University School of Medicine, Nashville, Tennessee; José R. Romero, MD,

University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, Arkansas; David Stephens, MD, Emory University School of

Medicine, Atlanta, Georgia; Peter Szilagyi, MD, University of California, Los Angeles (UCLA), Los Angeles, California; Helen Keipp Talbot, MD, Vanderbilt

University, Nashville, Tennessee; Emmanuel Walter, Jr., MD, Duke University School of Medicine, Durham, North Carolina.

Ex Officio Members: Mary Beth Hance, Centers for Medicare and Medicaid Services; Eric Deussing, MD, Department of Defense; Jane A. Kim, MD,

Department of Veterans Affairs; Doran Fink, MD, Food and Drug Administration; Narayan Nair, MD, Health Resources and Services Administration; Thomas

Weiser, MD, Indian Health Service; Tammy Beckham, National Vaccine Program Office; John Beigel, MD, National Institutes of Health.

Liaison Representatives: American Academy of Family Physicians, Pamela G. Rockwell, DO, Ann Arbor, Michigan; American Academy of Pediatrics, Yvonne

Maldonado, MD, Stanford, California; American Academy of Pediatrics, David Kimberlin, MD, Birmingham, Alabama; American Academy of Physician

Assistants, Marie-Michèle Léger, MPH, Alexandria, Virginia; American College Health Association, Susan Even, MD, Columbia, Missouri; American

College of Nurse Midwives, Carol E. Hayes, MN, Atlanta, Georgia; American College of Nurse Midwives, Pamela M. Meharry, PhD; American College of

Obstetricians and Gynecologists, Linda O’Neal Eckert, MD, Seattle, Washington; American College of Physicians, Jason M. Goldman, MD, Boca Raton,

Florida; American Geriatrics Society, Kenneth Schmader, MD, Durham, North Carolina; America’s Health Insurance Plans, Mark J. Netoskie, MD, Houston,

Texas; American Immunization Registry Association, Rebecca Coyle, MSEd, Washington DC; American Medical Association, Sandra Adamson Fryhofer,

MD, Atlanta, Georgia; American Nurses Association, Charles Rittle, MPH, Pittsburgh, Pennsylvania; American Osteopathic Association, Stanley Grogg, DO,

Tulsa, Oklahoma; American Pharmacists Association, Stephan L. Foster, PharmD, Memphis, Tennessee; Association of Immunization Managers, Christine

Finley, MPH, Burlington, Vermont; Association for Prevention Teaching and Research, Paul W. McKinney, MD, Louisville, Kentucky; Association of State

and Territorial Health Officials, Nathaniel Smith, MD, Little Rock, Arkansas; Biotechnology Industry Organization, Phyllis A. Arthur, MBA, Washington,

DC; Council of State and Territorial Epidemiologists, Christine Hahn, MD, Boise, Idaho; Canadian National Advisory Committee on Immunization,

Caroline Quach, MD, Montreal, Québec, Canada; Infectious Diseases Society of America, Carol J. Baker, MD, Houston, Texas; National Association of

County and City Health Officials, Matthew Zahn, MD, Santa Ana, California; National Association of County and City Health Officials, Jeffrey Duchin,

MD, Seattle, Washington; National Association of Pediatric Nurse Practitioners, Patricia A. Stinchfield, MS, St. Paul, Minnesota; National Foundation for

Infectious Diseases, William Schaffner, MD, Nashville, Tennessee; Mexico National Immunization Council and Child Health Program, Luis Duran, MD,

Mexico; National Medical Association, Patricia Whitley-Williams, MD, New Brunswick, New Jersey; Pediatric Infectious Diseases Society, Sean O’Leary,

MD, Colorado; Pediatric Infectious Diseases Society, Mark H. Sawyer, MD, San Diego, California; Pharmaceutical Research and Manufacturers of America,

David R. Johnson, MD, Swiftwater, Pennsylvania; Society for Adolescent Health and Medicine, Amy B. Middleman, MD, Oklahoma City, Oklahoma; Society

for Healthcare Epidemiology of America, David Weber, MD, Chapel Hill, North Carolina.

ACIP Anthrax Vaccine Work Group

ACIP Members: David S. Stephens, MD, Chair, Emory University School of Medicine, Atlanta, Georgia; Robert L. Atmar, MD, Baylor College of Medicine,

Houston, Texas; Sharon E. Frey, MD, St. Louis University Medical School, St. Louis, Missouri.

Ex Officio Members: Eric Espeland, PhD, Biomedical Advanced Research and Development Authority, Washington, DC; Chia-Wei Tsai, PhD,

Biomedical Advanced Research and Development Authority, Washington, DC; Amanda Zarrabian, MS, Biomedical Advanced Research and Development

Authority, Washington, DC; Eric Deussing, MD, Department of Defense, Atlanta, Georgia; Alexandra Worobec, MD, Food and Drug Administration,

Washington, DC; Julianne Clifford, PhD, Food and Drug Administration, Washington, DC; Judy Hewitt, PhD, National Institutes of Health, Bethesda,

Maryland; Kim Taylor, PhD, National Institutes of Health, Bethesda, Maryland.

Liaison Representatives: American College of Obstetricians and Gynecologists, Richard Beigi, MD, Pittsburgh, Pennsylvania; Infectious Diseases Society of

America, Kathleen Neuzil, MD, Baltimore, Maryland; American Academy of Pediatrics, James D. Campbell, MD, Golden, Colorado; National Association

of County and City Health Officials, Matthew Zahn, MD, Orange, California.

Invited Consultants: Wendy Keitel, MD, Baylor College of Medicine, Houston, Texas; Arthur Friedlander, MD, United States Army Medical Research

Institute of Infectious Diseases, Fort Detrick, Maryland; Phillip Pittman, MD, United States Army Medical Research Institute of Infectious Diseases, Fort

Detrick, Maryland; Andy Pavia, MD, University of Utah, Salt Lake City, Utah; Stacy Hall, MSN, Louisiana Office of Public Health, New Orleans, Louisiana.

CDC Contributors: Kate Hendricks, MD, CDC, Atlanta, Georgia; Jarad Schiffer, MS, CDC, Atlanta, Georgia; Conrad Quinn, PhD, CDC, Atlanta,

Georgia; Charles Rose, PhD, CDC, Atlanta, Georgia; Michael M. McNeil, MD, CDC, Atlanta, Georgia; Jennifer Wright, DVM, CDC, Atlanta, Georgia;

Yon Yu, PharmD, CDC, Atlanta, Georgia; Marie de Perio, MD, CDC, Cincinnati, Ohio.

Work Group Secretariat: William Bower, MD, CDC, Atlanta, Georgia.

ISSN: 0149-2195 (Print)

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