Anthrax Vaccine Dose Reduction

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Anthrax Vaccine Dose Reduction Route Change
Study
Jennifer G. Wright, DVM, MPH National Center for
Immunization and Respiratory Diseases Anthrax
Vaccine Research Program
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Anthrax

• Bacillus anthracis
• Gram positive, spore forming rod
• Enters skin, gastrointestinal tract, or lung
• Recognized as an illness for centuries
• Dramatic reduction in U.S. since early 1900s
• Current concern Use of anthrax as an agent of
  biowarfare
• Terror attacks via U.S. mail in fall 2001

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Threat

• Anthrax Spores the most likely bioweapon
• Sverdlosk incident, 1979 US mail incident, 2001
• Relatively easy and cheap to produce
• Can be stored for a long time
• Multiple dispersal methods
• Difficult to detect
• Inhalation form highly lethal
• gt80 mortality
• Can cause widespread illness and death among
  unprotected persons

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Anthrax Vaccine Adsorbed (AVA)

• Only vaccine licensed in the US to prevent
  anthrax pre-exposure
• Licensed regimen
• Subcutaneous administration
• 0, 2 and 4 weeks 6, 12, and 18 months
• Annual boosters
• Protective antigen (PA)
• Common to all anthrax strains
• Vaccine efficacy demonstrated against numerous
  anthrax strains in various animal studies
• Immune system primed to recognize and block PA

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Anthrax Toxins Building Blocks Effects

Edema Factor (EF) MW 89,000
Protective Antigen (PA) MW 83,000
Lethal Factor (LF) MW 90,000
Edema Toxin
Lethal Toxin
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mechanism of action of Anthrax Vaccine Adsorbed,
AVA
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Anthrax Toxins Building Blocks Effects

Edema Factor (EF) MW 89,000
Protective Antigen (PA) MW 83,000
Lethal Factor (LF) MW 90,000
Edema Toxin
Lethal Toxin
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mechanism of action of Anthrax Vaccine Adsorbed,
AVA
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Anthrax Vaccine Facts

• Manufactured
• Michigan Dept of Health until 1998
• Currently by Emergent BioSolutions
• Sterile, cell-free filtrate made from
  microaerophilic cultures of avirulent,
  non-encapsulated B. anthracis
• Aluminum hydroxide precipitate adjuvant

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http//www.emergentbiosolutions.com/pdf/emergent_
biothrax_us.pdf
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Anthrax Vaccine History, I

• 1950s Ft. Detrick/Merck formulation
• Cell culture filtrate precipitated with alum
• Brachman studies
• Brachman et al. Am J Pub Hlth 196252632.
• 1960s Lansing formulation
• Manufacturing process improved
• Increased PA concentration, purity, and potency
• 1970s Lansing formulation licensed
• Used data from Brachman studies (Ft. Detrick
  formulation)
• For those at high risk of exposure

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AVA History, II

• Limited data to support licensed regimen
• Animal studies and a single field evaluation
• 1997 DoD mandated immunizations
• Safety concerns raised
• Military experience with injection site reactions
• Unsubstantiated concerns
• Pilot Study by Col. Pittman
• Utilized reduced schedule and IM route
• Elicited similar antibody responses to licensed
  regimen
• Fewer injection site adverse events
• US Congress mandated Anthrax Vaccine Research
  Program (AVRP)

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AVRP Clinical Trial

• Optimize use, assess altered route of
  administration, evaluate surrogate markers of
  protection, evaluate immunologic memory
• Randomized, double-blind, placebo controlled
  Phase IV
• Data Safety Monitoring Board
• Dr. Stanley Plotkin, chair
• Inclusion
• Healthy adult 18-61 years old
• Exclusions - Specific allergies,
  immunosuppression, pregnancy

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Enrollment

• Total enrollment of 1564 civilian adults
• May 2002 - March 2004 (22 months)
• 51 are female
• Participant obligation 43 months
• First injection given May 2002
• Last injection given October 2007
• Study procedures
• 25 office visits
• 8 injections (6 dose priming, 2 boosters)
• 17 blood draws
• 22 in-clinic exams
• 8 patient diaries

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Schedule of Injections
AVAanthrax vaccine dose Ssaline dose
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Schedule of Injections
Interim Analysis
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Interim Analysis Results

• Demographics
• Mean age 38.4 years (range 18 to 61 at
  enrollment)
• lt30 years (30.0)
• 30-39 (24.0)
• 40-49 years (28.0)
• 50-61 years (18)
• Race distribution
• 76 White
• 19 Black
• 5 Other
• Ethnicity
• 95 non-Hispanic
• 5 Hispanic

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Interim Analysis Results

• Reactogenicity data
• Solicited adverse events
• Serologic data

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Results

• Adverse Events (Safety) Analysis
• Types of data collected
• In-clinic exam data (high specificity)
• AE summary data (high sensitivity)
• Additional information (duration, severity)
• In-clinic exams, phone reports, progress reports,
  and diaries
• Types of analyses conducted
• Intent to Treat (ITT) analysis
• According to Protocol (ATP) analysis
• ATP and ITT findings similar
• Immunogenicity Analysis
• Non-inferiority of anti-PA IgG
• Week 8
• Month 7 - Critical time point

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Safety Results

• Local (e.g. injection site warmth)
• All participants
• By gender
• Systemic (e.g. fatigue)
• All participants
• By gender
• Review of per dose data
• Review of repeated measures modeling
• Serious Adverse Events

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Local AE - WarmthPer Dose Data
Proportion with AE ()
Treatment Group
TRT-4IM less reactogenic than TRT-4SQ for all
doses
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Local AE SummaryTRT-4IM vs TRT-4SQ Comparison
All sig. differences indicate TRT-4IM is less
reactogenic than TRT-4SQ
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Local AE - WarmthRepeated Measures Models
Note control groups were dropped from the data
due to low cell counts
Mean Proportion with AE for all Doses ()
lt.0001
0.0068
0.0017
Treatment Group
Significant difference between TRT-4IM vs TRT-4SQ
(plt.0001) and F vs M (plt.0001)

Interaction exists
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Local AE SummaryRepeated Measures Models
All sig. differences indicate TRT-4IM is less
reactogenic than TRT-4SQ F reactions greater
than M
Y interactions
present between treatment and gender
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Systemic AE Fatigue Per Dose Data
Proportion with AE ()
Treatment Group
No diff. detected between TRT-4IM and TRT-4SQ
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Systemic AE SummaryTRT-4IM vs TRT-4SQ Comparison
No differences detected between TRT-4IM and
TRT-4SQ
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Systemic AE - FatigueRepeated Measures Models
Mean Proportion with AE for all Doses ()
Treatment Group
No significant difference between TRT-4IM vs
TRT-4SQ (p0.7159) Significant difference between
F vs M (p0.0391)
No interactions
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Systemic Endpoints SummaryRepeated Measures
Models
There were no significant differences in systemic
endpoints between 4IM and 4SQ, but there were
significant differences in reporting between men
and women. There were no interactions
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Serious Adverse Events

• Reporting SAEs is standard in clinical trials
• Whether or not the event in question could be
  related to administration of the drug under study
• A serious adverse event is one that results in
• Death, is life threatening, leads to or prolongs
  hospitalization, results in persistent/significant
  disability or congenital anomaly
• Assessment of causal relationship to study agent
• Unclassifiable
• Unrelated to very likely related
• Assessment made by Medical Monitor
• Medical Monitor remains blinded

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Serious Adverse Events

• Blinded assessments by independent Medical
  Monitor
• Interim analysis
• 51 reports of SAEs in 47 participants
• None were assessed as causally related to study
  agent
• As of June 9, 2008
• 229 reports of SAEs in 186 participants
• 9 events in 7 persons assessed as possibly
  related to the investigational agent

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Reactogenicity Summary

• TRT-4IM group experienced
• Local AEs at lower frequencies, lower severity
  and for shorter durations
• Route of administration did not significantly
  influence the occurrence or duration of systemic
  AEs
• Women reported significantly more AEs than men
• Differences between men and women for systemic
  events were statistically similar across
  treatment groups
• Even among the control groups
• Related AEs
• 9 Serious Adverse Events possibly

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Immunogenicity Endpoints Definitions

• Three primary endpoints (anti-PA specific IgG
  antibodies)
• Geometric mean concentration
• Geometric mean titer
• Proportion 4-fold rise in titer
• Three secondary endpoints
• Proportion 4-fold rise in concentration
• Proportion exceeding threshold titer
• Proportion exceeding threshold concentration

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Anti-PA IgG GMC is Non-inferior At Month 7
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Proportion of 4-Fold Responders is Non-inferior
At Week 8 Month 7
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Frequency of Non-Responders

• ATP, Unimputed Data
• 7 months
• 4-SQ 0/139
• 4-IM 0/145
• 3-IM 2/410 (0.5)
• PLAC 143/144 (99.3)
• 8 weeks
• 4-SQ 2/153 (1.3)
• 4-IM 3/154 (1.9)
• 3-IM 21/446 (4.7)
• PLAC 157/158 (99.4)

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AVRP Week 8 Analysis Serologic Conclusions

• High levels anti-PA IgG in all groups (GMC)
• Non-inferiority achieved - proportion of
  4-fold responders
• Significantly higher in females in 4-IM and 3-IM
  groups but not in the 4-SQ group (p0.12)
• General decrease in antibody response with
  increase in age
• Differences not evident at Month 7

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AVRP Month 7 Analysis Serologic Conclusions

• Primary decision time point
• Non-inferiority achieved all primary endpoints
• 4-SQ, 4-IM and 3-IM regimens provide equivalent
  immunological priming

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Interim Conclusions

• The clinical trial underwent an interim review by
  the FDA in 2005
• 4-SQ, 4-IM and 3-IM regimens provide equivalent
  immunological priming by month 7
• IM administration significantly reduces the
  occurrence of local AEs
• Biologic license change application (BLA)
• Add indication to drop the 2 week dose
• Add indication for IM administration
• Added language regarding missed doses
• Decision ???
• Still pending
• 3 letters from FDA

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Final Analysis (2008-09)

• Combine human clinical trial and animal data
• Determine what constitutes protection (onset and
  duration of immunity) in animals and bridge that
  to surrogate markers of protection in humans
• Look at human data
• 12m, 18m, and annual boosters

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Non-human Primate Data

• Several groups of NHP vaccinated
• Reduced schedule
• Challenged with anthrax spores 52, 128, 228 weeks
  after vaccination
• Vaccine dilution is highly correlated with
  survival
• 1/5 dilution high survival at 228 weeks
• Logistic modeling revealed that anti-PA IgG is
  the single best predictor of survival for NHPs
  when challenged with anthrax
• Other candidate assays being explored
• Data will be bridged to human data

Rose, BCT 2007
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Acknowledgements

• Jennifer Jarrell-Wilson
• Tom Taylor
• Han Li
• Heather Noland
• Freda Lyde
• Andrea Milton
• Stephanie Shields
• Nishi Patel
• Rita Desai
• John Walls
• Conrad Quinn
• Sandy Martin
• Darbi Abramson
• Hanan Dababneh
• Lydia Davis
• Evelene Steward-Clark
• Rhonda Thompson
• Sandy Martin
• Jamie Lewis

• Melissa Brawner
• Vera Semenova
• Natasha Brown
• Stephen Soroka
• Li X. Cronin
• Darlyne Smith
• Joe Caba
• Jarad Schiffer
• Safia Boghani
• Battelle Memorial Institute
• MilVax Agency, DoD
• US Army Medical Research Institute for Infectious
  Diseases, DoD
• Emergent BioSolutions
• Technical Resources International
• Data Safety Monitoring Board

• Scott Parker
• Mark Mulligan
• Col Janiine Babcock
• Wendy Keitel
• Hana El Sahly
• Gregory Poland
• Robert Jacobson
• Harry Keyserling
• Nina Marano
• Walter Holt
• Antoinette Seright
• Yvette Thompson
• Stacey Martin
• Chuck Rose
• Travis Wheeling
• Cristen Suhr
• Felicita David
• John Stamper
• Sonal Pathak

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CDC Team
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Questions?
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Timeline
Report to FDA
Enrollment
Responses to April 06 letter submitted to FDA
Response submitted
Interim analysis conducted first
1005 participants thru dose 4
Final analyses conducted
Final participant visit
FDA response letters received
Final report to FDA
3rd FDA letter
Mid 2009
Nov 2007
Late 2004
Sept 2005 April 2006
Aug 2007
Mar 2008
Feb 2005
Oct 2008
Apr 2008
May 2002- Mar 2004
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Pregnancy outcomes (n48)

• AVA FDA Pregnancy Category D
• Based on preliminary results of single study
• 41 - unrelated
• 5 - unlikely related
• i.e., incompetent cervix, club foot
• 1 possibly related
• Mother may have received study injection early in
  pregnancy based on date of last menstrual period
  and date of injection
• C-section for cephalopelvic disproportion
• 1 unknown
• outcome unknown

• As of June 9, 2008
• Blinded assessments

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ACIP Process

• Anthrax WG formed in October 2007
• Update and revise 2000 Statement and 2002
  Supplement into one document
• February 2008 - Presented data to ACIP
• Safety and immunogenicity
• June 2008 - Present additional data
• Vote on new statement in October 2008
• Key issues
• Vaccine recommendations for additional groups?
• Vaccines for pregnant women in a post-exposure
  situation?
• IM route and dropped 2 week dose, IF approved by
  FDA

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Brachman Study, 1962

• Combined Efficacy 92.5 (95 CI 65-100)
• 26 cases of anthrax
• 21cutaneous
• 19 in unvaccinated persons
• Placebos/refusals/persons not thought to be at
  risk
• 2 among incompletely vaccinated persons
• Inhalation anthrax
• 5 cases (4 fatal) in unvaccinated persons
• Placebos/refusals
• 0 cases among vaccinated persons
• Basis for licensure

Am J Public Health 196252632
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Inhalation Anthrax Vaccine Efficacy in Non-Human
Primates

• 65 monkeys vaccinated twice and challenged
• 62 survived all unvaccinated control monkeys
  died
• 95 vaccine protective efficacy against inhaled
  anthrax
• Correlates of immunity to infer from animals to
  humans have not been fully developed
• Part of the CDC Congressional mandate studies
  underway

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Shoulder Pain Reports

• Followed at the 2003 request of the DSMB
• New onset or exacerbation of existing pain with
  no alternative explanation
• 7 days beyond the first 2 weeks following
  injection
• 2003 DSMB review found no association with a
  particular treatment group
• Assessed by blinded Medical Monitor
• 36 cases among 32 participants
• 4 bilateral, 1 contralateral
• 31 homo- and uni-lateral
• Blinded assessments
• 20 possibly related to the study agent
• 5 probably related to the study agent

Masked review Feb 20, 2008
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Possibly Related SAEs

• Tear of shoulder supraspinatus tendon
• Generalized reaction night of 6th vaccine
• Bilateral pseudo tumor cerebri with bilateral
  disc edema
• New onset of generalized seizures, hydrocephalus
  consistent with aqueductal stenosis
• New onset bilateral arthralgia
• Invasive breast cancer
• 1 event bilateral
• 1 event unilateral
• November 2006 secondary review of VAERs and DoD
  data found no obvious trend for AVRP possibly
  related SAEs among persons receiving AVA

blinded analysis occurred after November 2006,
not included in VAERS review
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Independent Scientific Reviews(since 1985)

• FDA Advisory Panel on Bacterial Vaccines and
  Toxoids
• Federal Register, 1985
• Defense Health Board (DHB)
• advisory group to DoD, 1994-present
• Cochrane Collaboration, Oxford
• Vaccine, 1998, 2004
• Working Group on Civilian Biodefense
• JAMA, 1999, 2002
• CDCs Advisory Committee on Immunization
  Practices
• MMWR, 2000
• Anthrax Vaccine Expert Committee (AVEC)
• Pharmacoepidemiology and Drug Safety , 2002, 2004
• National Academy of Sciences (IOM), 2002
• FDA Review of VAERS reports
• supports FDAs Final Rule and Final Order, 2005

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NHP Efficacy References

• Ivins BE, Fellows PF, Pitt MLM, Estep JE, Welkos
  SL, Worsham PL. Efficacy of a standard human
  anthrax vaccine against Bacillus anthracis
  aerosol spore challenge in rhesus monkeys.
  Salisbury Med Bull 199687(suppl)125-6.
• Pitt MLM, Ivins BE, Estep JE, Farchaus J,
  Friedlander AM. Comparison of the efficacy of
  purified protective antigen and MDPH to protect
  non-human primates from inhalation anthrax.
  Salisbury Med Bull 199687 (suppl)130.
• Friedlander AM, Pittman PR, Parker GW. Anthrax
  vaccine Evidence for safety and efficacy against
  inhalational anthrax. JAMA 19992822104-6.
• Ivins BE, Pitt MLM, Fellows PF, et al.
  Comparative efficacy of experimental anthrax
  vaccine candidates against inhalation anthrax in
  rhesus macaques. Vaccine 1998161141-8.
• Pitt MLM, Little SF, Ivins BE, et al. In vitro
  correlation of immunity in a rabbit model of
  inhalational anthrax. Vaccine 2001194768-73.