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Anthrax Vaccine Dose Reduction

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Title: Anthrax Vaccine Dose Reduction


1
Anthrax Vaccine Dose Reduction Route Change
Study
Jennifer G. Wright, DVM, MPH National Center for
Immunization and Respiratory Diseases Anthrax
Vaccine Research Program
1
2
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

2
3
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

3
4
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

5
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
5
mechanism of action of Anthrax Vaccine Adsorbed,
AVA
6
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
6
mechanism of action of Anthrax Vaccine Adsorbed,
AVA
7
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

7
http//www.emergentbiosolutions.com/pdf/emergent_
biothrax_us.pdf
8
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

8
9
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)

10
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

11
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

12
Schedule of Injections
AVAanthrax vaccine dose Ssaline dose
13
Schedule of Injections
Interim Analysis
14
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

15
Interim Analysis Results
  • Reactogenicity data
  • Solicited adverse events
  • Serologic data

16
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

17
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

18
Local AE - WarmthPer Dose Data
Proportion with AE ()
Treatment Group
TRT-4IM less reactogenic than TRT-4SQ for all
doses
19
Local AE SummaryTRT-4IM vs TRT-4SQ Comparison
All sig. differences indicate TRT-4IM is less
reactogenic than TRT-4SQ
20
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
21
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
22
Systemic AE Fatigue Per Dose Data
Proportion with AE ()
Treatment Group
No diff. detected between TRT-4IM and TRT-4SQ
23
Systemic AE SummaryTRT-4IM vs TRT-4SQ Comparison
No differences detected between TRT-4IM and
TRT-4SQ
24
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
25
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
26
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

27
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

28
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

29
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

30
Anti-PA IgG GMC is Non-inferior At Month 7
31
Proportion of 4-Fold Responders is Non-inferior
At Week 8 Month 7
32
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)

33
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

34
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

35
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

36
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

37
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
38
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

39
CDC Team
40
Questions?
41
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
42
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

43
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

44
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
45
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

45
46
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
47
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
48
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

49
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.
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