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Introduction to ACAM2000 Smallpox Vaccine

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Title: Introduction to ACAM2000 Smallpox Vaccine


1
Introduction to ACAM2000 Smallpox Vaccine
  • David Wonnacott, PhD
  • Senior Vice President of Quality and Regulatory

2
Acambis Overview
  • Acambis develops novel vaccines to prevent and
    treat infectious diseases
  • Acambis locations
  • Cambridge, UK (Head Office) Canton, MA
    (manufacturing)
  • Cambridge, MA (RD) Rockville, MD
    (lyophilization, fill/finish)
  • 200 employees

3
Answering The Call
  • Critical demand for new and improved smallpox
    vaccine
  • Commercial manufacturing ceased after elimination
    of disease (1970s)
  • Strategic National Stockpile required new source
    of vaccine
  • ACAM2000 is unique
  • Needed to establish safety and efficacy in
    absence of disease
  • Highly targeted use managed by government agencies

4
Manufacturing
Todays Bioreactor ACAM2000, 2001 - ongoing
Original Bioreactor Calf skin vaccines, begun in
1805
5
Differences from Currently Licensed Smallpox
Vaccine
ACAM2000 Dryvax
Clonal, homogeneous(lt 0.4 genome changes) Uncloned, heterogeneous
Produced in cell culture without bovine serum Produced in calf skin
Enhanced, Modern cGMP Purification Method Purified to standards of the time (1970s)
Tested at current requirements, negative for adventitious viruses Tested to release standards of the time (1970s)
Less neurovirulent(mice, monkeys) Moderate neurovirulence (mice, monkeys)
Large scale production and surge capacity Original production methods
6
Parallel Clinical Development and Manufacturing
Timeline for Smallpox Vaccine (ACAM2000)
192.5 million doses delivered to SNS
CDC contract awarded to Acambis
Terrorist and anthrax attacks
Fast Track Designation
9/11 and 10/01
11/01
12/02
12/06
12/04
8/02
10/02
2/05
8/06
Clinical trial program (Phase I - III)
IND filed
BLA filed
SNS Strategic National Stockpile
7
Acambis Presentations
Smallpox Historical Overview John Neff, MD Seattle Childrens Hospital and Regional Medical Center
ACAM2000 Development Program Thomas P. Monath, MD Former Acambis Chief Scientific Officer
Smallpox Vaccine-Related Myocarditis Jay W. Mason, MD Prof of Medicine, Former Chief of Cardiology, University of Utah Prof of Medicine, Former Chair of Medicine, University of Kentucky
Risk Management Program Michael Watson, MD, PhD Executive Vice President of Research and Development
8
History of Smallpox Disease, Vaccination, and
Eradication
  • John Neff, MD
  • Seattle Childrens Hospital and Regional Medical
    Center

9
Topics to be Covered
  • History of Smallpox
  • Control, eradication, and potential for
    bioterrorism use
  • Smallpox Vaccination
  • Development, protection, adverse events
  • Description of Smallpox
  • Clinical types and expected mortality
  • Conclusions

10
History of Smallpox
11
Overview of Smallpox
  • First appeared possibly 1100 BC
  • Origin was probably from closely related animal
    pox viruses of the orthopox virus group
  • Smallpox became worldwide and endemic throughout
    Europe and caused pandemics with high mortalities
    in the Americas
  • Responsible for estimated 300 million deaths in
    20th century

12
Control of Smallpox
  • Variolation developed in Far East and introduced
    to Europe
  • 1796 First vaccinia-based vaccination by Edward
    Jenner
  • 1967 Enhanced WHO eradication program
  • 1972 Vaccination ended in US
  • 1977 Last natural case of smallpox (Somalia)
  • 1978 Last death/case of smallpox, lab acquired
    air vent system, Janet Parker in Birmingham,
    England
  • 1980 WHO declared smallpox eradicated
  • 1984 Official repositories of variola designated
    as CDC in Atlanta, GA and Vector in Novosibirsk,
    Russia

13
Smallpox Current Concerns
  • Soviet government bioweapons program
  • Aimed to produce smallpox in large quantities and
    adapt it for use in bombs and ICBMs
  • Industrial capacity capable of producing many
    tons of smallpox virus annually
  • Stocks in official repositories may not be secure
  • With break-up of Soviet Union, security at
    Vector was poor
  • Risk that rogue states did not destroy stocks
  • Could be used for bioterrorism purposes

14
Smallpox Vaccination
15
History of Vaccinia as Smallpox Vaccine
  • Vaccinia obtained from animals, presumably cows
    or horses
  • Member of Orthopox family
  • Related to both cowpox and variola
  • Initially propagated from person to person
  • The coordinated use of two standardized vaccinia
    strains, Lister and NYCBH, were responsible for
    eradicating smallpox worldwide by 1980

16
Evidence of Protection
  • Cutaneous Reaction (dermal take)
  • Major reaction correlates with
  • Protection against smallpox
  • Development or presence of neutralizing
    antibodies and T cells
  • Neutralizing Antibodies
  • Neutralizing antibodies correlate with protection
    against smallpox in humans
  • Mice and monkeys with neutralizing antibodies and
    T cell depletion are protected
  • Passive immunization provides some protection
  • T cells may also play an important role

17
Protection from Vaccination
  • Complete protection for three to five years
  • Partial protection for up to 25 years
  • Perhaps long-term protection against death

Case Fatality Rate of Smallpox After Importations into Western Countries During the Period 1950-1971 Case Fatality Rate of Smallpox After Importations into Western Countries During the Period 1950-1971
Successfully Vaccinated Case Fatality Rate
0-10 years before exposure 1.4
11-20 years before exposure 7
gt 20 years before exposure 11
Only after the exposure 29
Never 52
Fenner F et al. Smallpox and its Eradication, pp53
18
Historic Understanding of Adverse Events Data
from US Routine Vaccination Programs in 1960s
Complication of cases Comments
Progressive Vaccinia 1-7 cases per 1,000,000 vaccinations Mortality 25-60 Susceptibility CD4 T cell count lt 200/mm2
Eczema Vaccinatum 2-4 cases per 100,000 primary vaccinations 1 mortality 20-30 will be in contacts
Post Vaccinal Encephalitis 1-2 per 100,000 primary vaccinations 1-10 mortality or significant neurological impairment
Contact Vaccinia 2-6 cases per 100,000 primary vaccinations One-third of cases in children with history of eczema Required close body contact
Accidental Infections 1-6 cases per 1,000 No mortality Rare ocular impairment
Erythematous Reactions Occurs up to 1 per 100 primary vaccinations Very mild
19
Clinical Description of Smallpox
20
Smallpox
Communicability Day Symptoms Pathogenesis Symptoms Pathogenesis
NotContagious 1-3 NoSymptoms virus introd to resp tract
NotContagious 4-5 NoSymptoms appears in lymph nodes
NotContagious 6-11 NoSymptoms replicates in lymph system
NotContagious 12-13 FirstSymptoms Viremia, fever, backache, headache, nausea, malaise
Contagious 14 FirstSymptoms Viremia, fever, backache, headache, nausea, malaise
Contagious 15 Rash macules
VeryContagious 16-18 Rash papules
VeryContagious 19-20 Rash vesicles
Contagious 21-24 Rash pustules
Contagious 25 Rash scabs
Minimally Contagious 26-30 Rash scabs
21
Progression of Smallpox
Source CDC
22
Clinical Features of Smallpox
  • Discrete
  • Confluent
  • Flat
  • Hemorrhagic

23
Smallpox Discrete
  • Areas of normal skin between pustules even on face

Source CDC
24
Smallpox Confluent
  • Confluent rash on face and forearms

Source CDC
25
Smallpox Flat
  • Pustules confluent or semiconfluent appear flat

Source CDC
26
Smallpox Hemorrhagic
  • Widespread hemorrhage into skin, early and late
    forms, 98 case fatality

Source CDC
27
Smallpox Mortality
  • Mortality from infection with variola major in
    unvaccinated individuals can be up to 50

28
Conclusions
29
Conclusions
  • Smallpox is a devastating disease with a very
    high mortality rate in the non-immune
  • Vaccination historically associated with
    significant adverse events
  • Populations are immunologically vulnerable
    following eradication and end of vaccination
    programs
  • In the United States, few people have been
    vaccinated in 34 years

Continued
30
Conclusions (Continued)
  • As long as variola virus exists anywhere, there
    will be the need to have a smallpox vaccine
    available in the event of a bioterrorism threat
    or laboratory accident
  • It is in our best interest to have a modern
    smallpox vaccine available

31
ACAM2000 Smallpox Vaccine Development Program
  • Thomas P. Monath, MD
  • Former Acambis Chief Scientific Officer

32
Vaccine Development Goals Met
  • Purified clone derived from Dryvax (NYCBH
    vaccinia strain)
  • Well characterized seed lot free of adventitious
    agents
  • GMP manufacturing in cell culture (Vero) using
    modern standards
  • Meets all release specifications including
    potency 108 PFU/mL
  • Clinical safety similar to or better than Dryvax
  • Demonstrated clinical efficacy (some differences
    from Dryvax)

33
Indication/Use
  • Vaccination with ACAM2000 is indicated for
    protection of persons determined to be at high
    risk for smallpox infection
  • Not for routine vaccination of general population
  • Stored and controlled by Strategic National
    Stockpile (SNS)

34
Topics to be Covered
  • Introduction
  • Nonclinical data
  • Clinical data
  • Safety
  • Efficacy
  • Conclusions

35
Nonclinical Summary
  • Toxicology studies in mice and cynomolgus
    macaques inoculated IC show ACAM2000 less
    neurovirulent than Dryvax
  • ACAM2000 and Dryvax have similar immunogenicity
    in mice and monkeys
  • Both vaccines protect mice and cynomolgus
    macaques against lethal homologous and
    heterologous poxvirus challenge

36
ACAM2000 Is Less Neurovirulent than Dryvax 3-4
Day-old Mice Inoculated IC, n32/Group
37
ACAM2000 and Dryvax Elicit Similar Immune
Responses and Protect Cynomolgus Monkeys against
Lethal Monkeypox Challenge (3.8 x 107 PFU IV)
Parameter ACAM2000(n8) Dryvax(n8) Control(n8)
Immunization Immunization Immunization Immunization
Pock response rate (mm, D10) 8/8 (11.0) 8/8 (11.3) 0/8 (-)
N antibody(GMT, D30) 160 174 lt10
Challenge Challenge Challenge Challenge
Pox lesions None None gt100 per region
Temp. (2-3 days post challenge) Normal Normal gt103 C
Virus replication None throat in 3/8 plasma (6/8) PBMC (6/8) throat (8/8)
Death None None 8/8
38
Topics to be Covered
  • Introduction
  • Nonclinical data
  • Clinical data
  • Safety
  • Efficacy
  • Conclusions

39
ACAM2000 Clinical Studies
Phase Protocol Status Objectives Objectives Objectives Objectives Objectives Objectives Objectives Objectives
Phase Protocol Status Safety Cut. response Anti-body Doseresp. Lot consist. Tcells Viremia, shedding Nonspec serology
1 H-400-008 Naïve ? ? ?
1 H-400-002 Naïve ? ? ? ? ? ?
2 H-400-005 Naïve ? ? ? ?
2 H-400-003 PreviouslyVaccinated ? ? ? ?
3 H-400-009 Naïve ? ? ? ?
3 H-400-012 PreviouslyVaccinated ? ? ?
40
Subjects Evaluated for Safety
ACAM2000 ACAM2000 Dryvax Dryvax Total
Vaccinia- Naïven Previously Vaccinatedn Vaccinia- Naïve n Previously Vaccinatedn Total
Phase I 130 0 30 0 160
Phase II 304 305 49 52 710
Phase III 873 1371 289 448 2981
Sub-total 1307 1676 368 500
Total 2983 2983 868 868 3851
Phase III study enrollment curtailed due to
myocarditis AEs. Planned enrollment 2040
ACAM2000 and 680 Dryvax
41
Phase III Subject DispositionSafety Population
H-400-009 (Vaccinia-Naïve) H-400-009 (Vaccinia-Naïve) H-400-012 (Previously Vaccinated) H-400-012 (Previously Vaccinated)
ACAM2000n873 Dryvax n289 ACAM2000n1371 Dryvax n448
Vaccinated n () 873 (100) 289 (100) 1371 (100) 448 (100)
Completed n () 863 (99) 287 (99) 1362 (99) 442 (99)
Withdrew n () 10 (1) 2 (lt1) 9 (lt1) 6 (1)
42
Phase III DemographicsSafety Population
H-400-009 (Vaccinia-Naïve) H-400-009 (Vaccinia-Naïve) H-400-012 (Previously Vaccinated) H-400-012 (Previously Vaccinated)
ACAM2000n873 Dryvax n289 ACAM2000n1371 Dryvax n448
Age(yr, mean) 23 23 48.9 49.2
Male 66 63 50 48
Caucasian 76 71 78 78
African-American 11 14 10 11
43
Common Adverse Events
  • Expected AEs known to be associated with
    smallpox vaccinations
  • Inoculation site reactions, lymphadenitis,
    feverishness, chills, fatigue, malaise, myalgia
  • The incidence of these AEs was higher for
    Dryvax than ACAM2000

44
Solicited Adverse Events Occurring in 10 of
Subjects by Treatment Group, Phase III
Vaccinia-Naïve Vaccinia-Naïve Vaccinia-Naïve Previously Vaccinated Previously Vaccinated Previously Vaccinated
MedDRA Preferred Term ACAM 2000 (n873) Dryvax (n289) p-value ACAM 2000 (n1371) Dryvax (n448) p-value
At least 1 AE 99 100 0.466 97 99 0.012
Injection site pruritus 92 96 0.032 82 93 lt0.001
Injection site erythema 74 79 0.098 61 72 lt0.001
Injection site pain 67 72 0.095 37 47 lt0.001
Lymph node pain 57 69 lt0.001 19 27 lt0.001
Headache 50 52 0.498 32 37 0.049
Fatigue 48 56 0.035 34 41 0.009
Injection site swelling 48 57 0.010 28 42 lt0.001
Myalgia 46 51 0.197 27 33 0.022
Malaise 37 42 0.163 28 33 0.048
Feeling hot 32 34 0.561 20 25 0.011
Erythema 22 24 0.464 24 24 1.000
Rigors 21 23 0.564 12 17 0.017
Nausea 19 22 0.273 10 14 0.039
Diarrhea 16 12 0.059 12 17 0.003
Exercise tolerance decreased 11 12 0.671 8 11 0.025
Rash 11 10 0.913 6 6 0.647
Lymphadenopathy 8 12 0.060 6 6 0.563
45
Serious Adverse Events All Studies
Vaccinia-Naïve Vaccinia-Naïve Previously Vaccinated Previously Vaccinated
ACAM2000(n1307) Dryvax?(n368) ACAM2000(n1676) Dryvax?(n500)
Deaths 0 0 0 0
At least 1 SAE 13 (1) 4 (1) 6 (lt1) 3 (1)
Myocarditis / myopericarditis 7 (0.54) 3 (0.82) 0 0
Atrial fibrillation 0 0 1 (lt1) 0
Coronary artery disease 0 0 0 1 (lt1)
Chest discomfort 0 0 1 (lt1) 0
Chest pain 0 0 1 (lt1) 0
Hypersensitivity 0 0 0 1 (lt1)
Appendicitis 1 (lt1) 0 1 (lt1) 0
Generalized vaccinia (cowpox) 0 0 0 1 (lt1)
HIV test positive subject vaccinated 0 0 1(lt1) 0
Convulsions 1 (lt1) 0 0 0
Pregnancy during on-study phase 4 (lt1) 0 1 (lt1) 0
Urticaria 0 1 (lt1) 0 0
46
Myocarditis
  • Prospective case ascertainment Phase I
    (H-400-002) and Phase III
  • ECGs at screening, Day 10 and 21 (Phase III) or
    screening and Day 15 (Phase I)
  • Troponin I and/or CK-MB at screening and Day 10
    (Phase III) or Day 15 (Phase I)
  • Provoked cardiac AEs (clinic visits, diaries)
  • Myocarditis seen only in vaccinia-naïve subjects
  • Previous under-reporting based on passive
    surveillance and symptomatic cases only

47
Myocarditis Phase I (H-400-002) and Phase III
(Vaccinia-naïve Subjects, Standardized Case
Ascertainment)
ACAM2000n903 Dryvaxn319
Myocarditis 6 cases (6.6/1000) 2 symptomatic 1 hospitalized 3 cases (9.4/1000) 1 symptomatic 1 hospitalized
Follow-up 6/6 resolved 2/3 resolved 1 with ? LVEF
48
Topics to be Covered
  • Introduction
  • Nonclinical data
  • Clinical data
  • Safety
  • Efficacy
  • Conclusions

49
Vaccine Efficacy
  • Efficacy cannot be demonstrated in disease
    setting due to eradication of smallpox
  • Cutaneous Response is a generally accepted
    surrogate of protection (WHO, ACIP)
  • Neutralizing Antibodies are a correlate of
    protection
  • May be more accurate reflection of vaccine
    effectiveness in previously vaccinated subjects
    with modified takes
  • Historical data suggest relatively low titers
    are protective
  • Mack et al., 1972 (protective titer gt132)
  • Sarkar et al., 1975 (protective titer gt120)

50
Phase III Trials Efficacy Analyses
Co-Primary Statistical Method Secondary
Cutaneous Response Rate Non-inferiority Exclude margin of superiority of Dryvax gt5 (naïve) or gt10 (prev. vacc.) Covariate analyses (baseline immunity, H-400-012)
GMT Non-inferiority Ratio of ACAM2000Dryvax GMT at least 0.5 (log10 -0.301) Covariate analyses (baseline immunity, H-400-012) Titer freq. distribution Fold-increase in PRNT Seroconversion rates
51
Phase III Endpoint Cutaneous Response
Vaccinia-Naïve (Study H-400-009) Vaccinia-Naïve (Study H-400-009) Previously Vaccinated (Study H-400-012) Previously Vaccinated (Study H-400-012)
ACAM 2000 n776 Dryvax n257 ACAM 2000 n1189 Dryvax n388
Positive n () 747 (96) 255 (99) 998 (84) 381 (98)
97.5 CI (Criteria) -4.67 (gt -5.0, lower bound of difference in rates) -4.67 (gt -5.0, lower bound of difference in rates) -17 (gt -10.0 , lower bound of difference in rates) -17 (gt -10.0 , lower bound of difference in rates)
Non-inferiority Endpoint met? Yes Yes No No
  • ACAM2000 non-inferior to Dryvax in
    vaccinia-naïve subjects
  • ACAM2000 has lower cutaneous response rate than
    Dryvax in previously vaccinated subjects

52
Cutaneous Response RatesPreviously Vaccinated
(Phase III), Adjusted for Baseline Antibody
Titer (Antibody Evaluable Population)
Baseline Titer Statistic Treatment Group Treatment Group
Baseline Titer Statistic ACAM2000 (n706) Dryvax? (n364)
lt110 Cutaneous Response 151/161 (94) 86/88 (98)
110 120 Cutaneous Response 158/186 (85) 107/108 (99)
140 180 Cutaneous Response 168/199 (84) 93/94 (99)
?1160 Cutaneous Response 116/160 (73) 72/74 (97)
  • Subjects without detectable residual immunity
    have high vaccination success rate to ACAM2000
    (94)
  • Higher sensitivity to interference by residual
    immunity reflects relative attenuation of
    ACAM2000 vs. Dryvax

53
Neutralizing Antibody Fold-IncreasePreviously
Vaccinated (Phase III), Adjusted for Baseline
Antibody Titer (Antibody Evaluable Population)
Baseline Titer Statistic Treatment Group Treatment Group
Baseline Titer Statistic ACAM2000 (n706) Dryvax? (n364)
lt110 Fold-Increase (Geometric Mean Titer) 29.6 36.4
110 120 Fold-Increase (Geometric Mean Titer) 13.3 23.8
140 180 Fold-Increase (Geometric Mean Titer) 5.9 10.9
?1160 Fold-Increase (Geometric Mean Titer) 2.2 4.8
54
Phase III Endpoint Neutralizing Antibody
Vaccinia-Naïve (Study H-400-009) Vaccinia-Naïve (Study H-400-009) Previously Vaccinated (Study H-400-012) Previously Vaccinated (Study H-400-012)
ACAM 2000 n565 Dryvax n190 ACAM 2000 n734 Dryvax n376
GMT 166 255 286 445
97.5 CI (Criteria) -0.307 ( -0.301) -0.307 ( -0.301) -0.275 ( -0.301) -0.275 ( -0.301)
Non-inferiority Endpoint met? No No Yes Yes
lower bound on difference in mean log10 GMT lower bound on difference in mean log10 GMT lower bound on difference in mean log10 GMT lower bound on difference in mean log10 GMT lower bound on difference in mean log10 GMT
  • 1.5-fold lower GMT following ACAM2000 vs.
    Dryvax
  • Non-inferiority endpoint narrowly missed in
    primary vaccination, met in previously vaccinated
    subjects

55
gt90 of Subjects Have Antibody Titers Greater
than Historical Protective Level
56
Categorical and Median T cell responsesNaïve
Subjects (H-400-002)
57
T cell (?-IFN-ELISPOT) Responses (H-400-002)
Positive response gt20 spot-forming cells/106
58
Conclusions
  • Modern processes and QC methods used in
    large-scale manufacturing of ACAM2000
  • Safety assurance greater than production on calf
    skin (potential for adventitious agents)
  • 75 lots,192.5M doses deposited in SNS
  • Purified clonal vaccine, less neurovirulent in
    animal models
  • Immunogenic and protective against lethal pox in
    4 animal models, 2 species
  • Clinical data demonstrate safety and tolerability
    equivalent to or better than Dryvax
  • Vaccinia-associated myocarditis incidence
    approximately 1 in 150

59
Conclusions (Continuing)
  • Primary indicators of immunity support ACAM2000
    efficacy in naïve subjects
  • Cutaneous Response
  • 96 take rate
  • Non-inferior to Dryvax
  • Neutralizing Antibody
  • High GMT (166)
  • gt90 with neutralizing antibody titers above
    putative protective level of 132
  • Narrowly missed statistical non-inferiority
    endpoint in naïve subjects (-.307 vs -.301)
  • Robust T cell responses similar to Dryvax
  • Important for immunological memory

60
Conclusions (Continuing)
  • Primary indicators of immunity support ACAM2000
    efficacy in previously-vaccinated
  • Neutralizing Antibody
  • May be better measure of vaccine effectiveness
    due to modified takes
  • GMT (286) higher than following primary
    vaccination
  • gt95 with neutralizing antibody titers above
    putative protective level of 132
  • Non-inferior to Dryvax
  • Cutaneous Response
  • 84, lower than Dryvax, not non-inferior
  • 94 in subjects without baseline antibody

61
Mechanisms and Detection of Myocarditis
andOutcomes and Incidence of Smallpox
Vaccine-Related Myocarditis
  • Jay W. Mason, MD
  • Professor of Medicine, Former Chief of
    Cardiology, University of Utah
  • Professor of Medicine, Former Chair of Medicine,
    University of Kentucky

62
Topics
  • Mechanism of Viral Myocarditis
  • Detection of Myocarditis
  • Outcomes of Myocarditis
  • Classic myocarditis vs.
  • Smallpox vaccine-related myocarditis
  • Incidence of Smallpox Vaccine-related Myocarditis

63
Mechanism of Viral Myocarditis
64
Triphasic Disease Process in Classic Myocarditis
Autoimmune Injury
Viral Replication
Dilated Cardiomyopathy
65
Detection of Myocarditis
66
Current Methods for Diagnosis
  • Endomyocardial biopsy
  • Histology, inflammatory markers, viral nucleic
    acid sequences
  • Imaging
  • MRI, ultrasound, nuclear scintigraphy
  • Circulating Immune markers
  • ECG
  • Sensitivity 47, Morgera 1992
  • Troponin
  • Sensitivity 34 - 71, Specificity 86 - 94
  • Clinical History
  • Sensitivity 53, USMTT

67
ACAM2000 Clinical Trials Myocarditis Case Summary
Subject Number Clinical Symptoms ECG Troponin ECHO
2063 No Symptoms
023190 No Symptoms
056111 No Symptoms
094114 No Symptoms
004103 Mild Ex intol
054106 CP, DOE, Palps, ? Ex tol
048116 CP, ? Ex tol
080112 DOE, Palps
1238 CP
065137 Equivocal
Total 6 / 10 9 / 10 6 / 10 3 / 10
Subjects Hospitalized Case not reviewed by
CAP, but by Medical Monitor
68
ACAM2000 Clinical Trials Myocarditis Case
Summary (Continued)
CAP Classification Subject Tx Day of Onset Outcome
Suspected Subclinical Myocarditis 2063 023190 ACAM2000 ACAM2000 14 9 Resolved Resolved
Probable Subclinical Myocarditis 056111 094194 ACAM2000 ACAM2000 10 9 Resolved Resolved
Suspect Myocarditis 004103 Dryvax 20 Resolved
Probable Myocarditis 048116 080112 054106 1238 065137 ACAM2000 ACAM2000 Dryvax ACAM2000 Dryvax 11 9 11 10 9 Resolved Resolved Resolved Resolved Ongoing
69
Outcomes of Myocarditis
70
Outcome in US Myocarditis Treatment Trial
71
Incidence of Smallpox Vaccine-Related Myocarditis
72
Incidence of Myocarditis Depends on Primary
Diagnostic Criteria Recent Experience
Consistent with the Past
Source Year Vaccinees Cases Incidence Resolution Onset Death
Self-Reporting Self-Reporting Self-Reporting Self-Reporting Self-Reporting Self-Reporting Self-Reporting Self-Reporting
New York 1947 5M 1 0.00002 N/A NR 1
Finland 1977 1979 60,000 10 0.02 UNK NR 1
DOD Dryvax 2002 2007 1.2M 140 0.01 8 / 53 Unresolved lt26d 3
CDC Dryvax 2002 2007 40,449 21 0.05 3 Unresolved lt44d 0
ECG and/or Serum Markers ECG and/or Serum Markers ECG and/or Serum Markers ECG and/or Serum Markers ECG and/or Serum Markers ECG and/or Serum Markers ECG and/or Serum Markers ECG and/or Serum Markers
Helle (Finland) 1974 234 8 3.4 6 Resolved, 2 LTFU NR 0
Ahlborg (Swe) 1963 286 (re-vaccinees) 3 1.0 Not followed up NR 0
Acambis-Dryvax 2003 2004 289 (P3) 868 (all studies) 3 3 1.04 0.35 1 Case Unresolved lt21d 0
ACAM2000 2003 2004 873 (P3) 2983 (all studies) 5 7 0.57 0.23 All Resolved lt12d lt14d 0
At autopsy Publication unclear whether death
was in a smallpox vaccinee 2 cases classified
as possible Vaccinia-related myocarditis,
although neither case has confirmed cause of
death as myocarditis 1 case is still pending
73
Conclusions
  • Incidence of smallpox vaccine-related myocarditis
  • Highly dependent on case ascertainment and
    definition
  • lt 1 with most rigorous case ascertainment and
    definition
  • Not increased by ACAM2000
  • Spontaneous resolution in majority
  • Clinical history, troponin and ECG
  • Only practical large scale detection methods
  • Sensitivity and specificity adequate

74
ACAM2000 Risk Management Plan (PVG Program
RiskMAP)
  • Michael Watson, MD, PhD
  • Executive Vice President of Research and
    Development

75
ACAM2000 Clinical Trial Experience
  • ACAM2000 well tolerated
  • Similar or better safety profile to Dryvax for
    all AEs
  • Relatively few SAEs
  • Most important finding
  • Myocarditis in ACAM2000 (0.57) and Dryvax
    (1.04)
  • Case ascertainment definition dependent
  • ACAM2000 Phase III prospectively assessed ECG,
    enzymes symptoms

76
ACAM2000 PVG Program Goals
  • Monitor for rarer SAEs signal detection
  • Establish more precise incidence rate for
    possible myocarditis
  • Assess short, medium long-term outcome for
    possible myocarditis cases

77
Elements of ACAM2000 PVG Program
ACAM2000 licensure ACAM2000 licensure Year 1 Year 1 Year 2 Year 2 Year 3 Year 3
General Signal detection case finding for Myocarditis Registry Routine PVG (spontaneous reporting) Enhanced Surveillance (ESAV)
Prospective trial case finding for Myocarditis Registry Phase IV Trial
Long-term Follow-up Myocarditis Registry
Routine PVG and myocarditis registry continue
through life of product
78
ACAM2000 Routine Pharmacovigilance
  • In collaboration with DoD and CDC
  • Expedited reporting agreement with FDA
  • Meet FDA Regulatory Reporting Req
  • VAERS for spontaneously reported events
  • PSURs (quarterly x 3 years annually thereafter)
  • Foreign reports, literature
  • Acambis PVG Validated Safety Database (Argus)
    operational
  • Cardiac AEs entered into registry
  • Under-reporting expected of any passive system

79
ACAM2000 Enhanced Surveillance Program
  • In collaboration with DoD
  • Objective collect larger cohort of possible
    myocarditis for follow-up
  • Identify cases for Myocarditis Registry
  • Signal detection and SAEs and AEs of interest

80
Enhanced Surveillance (gt100,000)
Vaccination
Direct from subject, cards email
Symptom Solicitation at days 10 21
Potential signals/AEs of interest
Adjudication Committee
Cardiac events of interest
Myocarditis Registry
81
ACAM2000 Phase IV Trial (N10,000)
  • Goals
  • More precise estimate of incidence of possible
    myocarditis in vaccine recipients, according to
    symptoms, signs, labs and investigations
  • Assess short, medium long-term outcome of
    events
  • Identify other SAEs of interest

82
ACAM2000 Phase IV Trial
  • In collaboration with DoD (deployable troops,
    informed consent)
  • Initiate within 12 months of product licensure
  • Multicenter safety trial at 3-5 large military
    posts
  • Potentially 10,000 (to be defined) participants
    vaccinated with ACAM2000 alone
  • Investigating possible control group
  • Anticipated time to complete 2 years from first
    subject in
  • Ongoing organizational discussions to align with
    DoD priorities

83
Phase IV Schedule of Events
N10,000
Screening, informed consent
Vaccination
Medical visit
Follow-Up forPossibleMyocarditis
If positive
Troponin,Symptoms
Day 10Assessment
Medical visit
Subject F/UScheduling(as required)
Other identified events
Follow-up
Day 21Assessment
84
ACAM2000 Myocarditis Registry
  • Maintained by DoD Vaccine Health Care Centers
    (VHC)
  • Objective ascertain long-term outcome of acute
    possible myocarditis related to smallpox
    vaccine
  • Follow-up period to a minimum of 2 years after
    onset (annual visits) and longer for cases that
    remain symptomatic

85
Other Action under Consideration
  • Retrospective cohort or case control study
  • Vaccination against smallpox was common prior to
    1970
  • No evidence for smallpox vaccine as cause of
    significant numbers of Dilated Cardiomyopathy
    (DCM)
  • Cohort or case control studies could assess the
    strength of association of smallpox vaccine with
    DCM 20-40 years later
  • CDC
  • Framingham
  • Swedish or Finnish military cohorts

86
Risk Minimization Action Plan(RiskMAP)
87
Targets for Risk Minimization
  • Potential vaccinees
  • Vaccinees
  • Contacts of vaccinees
  • Vaccinating physicians
  • Follow-up physicians

88
Risks to be Minimized
  • Auto-inoculation especially ocular
  • Secondary transmission
  • Eczema in primary and secondary contacts
  • Immuno-compromised
  • Pregnancy
  • Cardiac adverse events
  • Encephalitis
  • Allergy to vaccine and/or components

89
Practical and Accessible Tools
90
Auto-innoculation and Secondary Transmission
  • Extensive, repeated, clear advice have resulted
    in far fewer EV and secondary transmission cases
    than previously seen

91
Eczema in Vaccinee and Contacts
  • Screening Form 600 currently used
  • Form records responses to
  • Does subject have atopic dermatitis or other
    chronic skin conditions
  • Did subject have atopic dermatitis as a child
  • Health status of people in the subjects
    household
  • In light of recent case of EV, visibility and
    guidance will be further increased

92
Immuno-compromised
  • Screening Form 600 currently used
  • Form records information regarding
  • Subjects immune system (e.g., immuno-deficiency
    due to cancer treatment, transplantation, AIDS,
    other conditions)
  • Subjects HIV status

93
Inadvertent Use In Pregnancy
  • Screening Form
  • Pregnancy Test

94
Minimization of Cardiac AEs
  • Clear screening for and exclusion of Cardiac risk
    factors
  • History of angina
  • An earlier heart attack
  • Artery disease
  • Congestive heart failure
  • Cardiomyopathy
  • Stroke, mini stroke,
  • Chest pain or shortness of breath with activity
  • Or three or more of the following cardiac risk
    factors
  • Current smoker or tobacco user
  • High blood pressure
  • High cholesterol or triglycerides
  • High blood sugar
  • Heart condition before age 50 in a parent,
    brother, or sister

95
Other Risk Minimization/Management Elements for
Myo/Pericarditis
  • Vaccination 30-60 days prior to deployment
    cases appear mean of 11 days after vaccination
  • Algorithm for identifying and managing potential
    cases of myo/pericarditis
  • 6 month non-deployable period and specific
    physical exercise form for all potential cases
  • Ongoing immuno-genetic studies to try and
    identify at-risk groups
  • 140 cases of myo/pericarditis among 1.2 million
    vaccinees

96
Encephalitis
  • Very rare
  • No clearly identified risk factors
  • Unlikely to be pre-existing neurological
    conditions in active military personnel

97
Compliance
  • DoD Regional Analysts conduct hospital visits to
    check compliance with use of screening forms and
    educational materials

98
Planned Additional Risk Minimization Tools
  • Medication guide first for a vaccine
  • Work closely with DoD and CDC to ensure
    consistency and sharing of information and
    explore tools for assessing compliance and impact
    of tools

99
Summary Recommendations
  • Extensive group of proven tools available
  • Increase visibility of eczema warnings
  • Ongoing work to try to identify risk factors for
    myo/pericarditis
  • Explore tools to assess vaccinee and physician
    compliance
  • Ensure ongoing review and revision as required
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