# Presentation: 657118

## Introduction to ACAM2000 Smallpox Vaccine

**David Wonnacott, PhD**
*Senior Vice President of **Quality and Regulatory*

## Acambis Overview

**Acambis develops novel vaccines to prevent and treat ****infectious diseases**
**Acambis locations:**
**Cambridge, UK (Head Office)****	**–**	****Canton, MA (manufacturing)**
**Cambridge, MA (R&D)****	**–**	****Rockville, MD (lyophilization, fill/finish)**
**200+ employees**

## “Answering The Call”

**Critical demand for new and improved smallpox vaccine**
**Commercial manufacturing ceased after elimination of disease (1970’s)**
**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**

## Manufacturing

**Today’s Bioreactor**
- ACAM2000, 2001 - ongoing

**Original Bioreactor**
- Calf skin vaccines, begun in 1805

**Notes:**
Shaved about 12-18 months off clinical trial programme
Dryvax no longer licensed
Rapid interested required so went for fixed price
Won because:
Technically proficient
Time advantage
Capacity
Price

## Differences from Currently Licensed Smallpox Vaccine

| ACAM2000 | Dryvax® |
| --- | --- |
| Clonal, homogeneous(< 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 (1970’s) |
| Tested at current requirements, negative for adventitious viruses | Tested to release standards of the time (1970’s) |
| Less neurovirulent(mice, monkeys) | Moderate neurovirulence (mice, monkeys) |
| Large scale production and surge capacity | Original production methods |

**Differences from Currently Licensed Smallpox Vaccine**

## Parallel Clinical Development and Manufacturing Timeline for Smallpox Vaccine (ACAM2000)

**192.5 million doses**
**delivered to SNS***

**Parallel Clinical Development and Manufacturing Timeline for Smallpox Vaccine (ACAM2000)**

**9/11 ****and 10/01**

**8/02**

**Clinical trial program**
**(Phase I - III)**

**CDC contract**
**awarded to**
**Acambis**

**11/01**

**IND**
**filed**

**10/02**

**12/02**

**2/05**

**8/06**

**12/06**

**Terrorist ****and anthrax**
**attacks**

**BLA filed**

**12/04**

**Fast Track**
**Designation**

*** SNS – Strategic National Stockpile**

## Acambis Presentations

| Smallpox Historical Overview | John Neff, MD
Seattle Children’s 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 |

## History of Smallpox Disease, Vaccination, and Eradication

**John Neff, MD**
*Seattle Children’s Hospital and **Regional Medical Center*

## 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**

## History of Smallpox 

## 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 20****th**** century**

## 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**

## 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**

## Smallpox Vaccination

## 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**

## 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**

## 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 |  |
| --- | --- |
| Successfully Vaccinated | Case Fatality Rate |
| 0-10 years before exposure | 1.4% |
| 11-20 years before exposure | 7% |
| > 20 years before exposure | 11% |
| Only after the exposure | 29% |
| Never | 52% |

***Fenner F et al. Smallpox and its Eradication, pp53***

## 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 < 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 |

## Clinical Description of Smallpox

## Smallpox

| Communicability | Day | Symptoms & Pathogenesis |  |
| --- | --- | --- | --- |
| NotContagious | 1-3 | NoSymptoms | virus intro’d to resp tract |
|  | 4-5 |  | appears in lymph nodes |
|  | 6-11 |  | replicates in lymph system |
|  | 12-13 | FirstSymptoms | Viremia, fever, backache, headache, nausea, malaise |
| Contagious | 14 |  |  |
|  | 15 | Rash | macules |
| VeryContagious | 16-18 |  | papules |
|  | 19-20 |  | vesicles |
| Contagious | 21-24 |  | pustules |
|  | 25 |  | scabs |
| Minimally Contagious | 26-30 |  |  |

## Progression of Smallpox

**Source:  CDC**

## Clinical Features of Smallpox

**Discrete**
**Confluent**
**Flat**
**Hemorrhagic**

## Smallpox – Discrete

- Areas of normal skin between pustules even on face

**Source:  CDC**

## Smallpox – Confluent 

- Confluent rash on face and forearms

**Source:  CDC**

## Smallpox – Flat 

- Pustules confluent or semiconfluent – appear flat

**Source:  CDC**

## Smallpox – Hemorrhagic

- Widespread hemorrhage into skin, early and late forms, 98% case fatality

**Source:  CDC**

## Smallpox Mortality

**Mortality from infection with variola major in unvaccinated individuals can be up to 50% **

## Conclusions

## 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*

## 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***

## ACAM2000 Smallpox Vaccine Development Program

**Thomas P. Monath, MD**
*Former Acambis Chief Scientific Officer*

**Notes:**
Suggest change title to pre-BLA meeting (and give date). It is more than just phase 3 trials

## 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 ****≥ 10****8**** PFU/mL**
**Clinical safety similar to or better than Dryvax****®**
**Demonstrated clinical efficacy (some differences ****from Dryvax****®****)**

## 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)**

## Topics to be Covered

**Introduction**
**Nonclinical data**
**Clinical data**
**Safety**
**Efficacy**
**Conclusions**

## 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**

**Notes:**
Explain relevance of tox studies to PVE—most feared AE

## ACAM2000 Is Less Neurovirulent than Dryvax® 3-4 Day-old Mice Inoculated IC, n=32/Group

**ACAM2000 Is Less Neurovirulent than Dryvax****®**** *****3-4 Day-old Mice Inoculated IC, n=32/Group***

## ACAM2000 and Dryvax® Elicit Similar Immune Responses and Protect Cynomolgus Monkeys against Lethal Monkeypox Challenge (3.8 x 107 PFU IV) 

| Parameter | ACAM2000(n=8) | Dryvax®(n=8) | Control(n=8) |
| --- | --- | --- | --- |
| Immunization |  |  |  |
| Pock response rate (mm, D10) | 8/8 (11.0) | 8/8 (11.3) | 0/8 (-) |
| N antibody(GMT, D30) | 160 | 174 | <10 |
| Challenge |  |  |  |
| Pox lesions | None                     | None | >100 per region |
| Temp. 
(2-3 days post challenge) | Normal | Normal | >103° C |
| Virus replication | None | + throat in 3/8 | ++plasma (6/8)
++PBMC (6/8)
+++throat (8/8) |
| Death | None | None |             8/8 |

## Topics to be Covered

**Introduction**
**Nonclinical data**
**Clinical data**
**Safety**
**Efficacy**
**Conclusions**

## ACAM2000 Clinical Studies

| Phase | Protocol | Status | Objectives |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  |  |  | Safety | Cut. response | Anti-body | Doseresp. | Lot consist. | Tcells | Viremia, shedding | Nonspec serology |
| 1 | H-400-008 | Naïve |  |  |  |  |  |  |  |  |
| 1 | H-400-002 | Naïve |  |  |  |  |  |  |  |  |
| 2 | H-400-005 | Naïve |  |  |  |  |  |  |  |  |
| 2 | H-400-003 | PreviouslyVaccinated |  |  |  |  |  |  |  |  |
| 3 | H-400-009 | Naïve |  |  |  |  |  |  |  |  |
| 3 | H-400-012 | PreviouslyVaccinated |  |  |  |  |  |  |  |  |

## Subjects Evaluated for Safety

|  | ACAM2000 |  |  | Dryvax® |  |  | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | Vaccinia- Naïven | Previously
Vaccinatedn |  | Vaccinia- Naïve n | Previously
Vaccinatedn |  |  |
| 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 |  |  | 868 |  |  | 3851 |

- *	Phase III study enrollment curtailed due to myocarditis AEs. Planned enrollment 2040 ACAM2000 and 680 Dryvax®

**Notes:**
TOM:  please speak to curtailment due to CT clinical hold / risk of myocarditis

## Phase III Subject DispositionSafety Population

|  | H-400-009 
(Vaccinia-Naïve) |  |  | H-400-012 
(Previously Vaccinated) |  |
| --- | --- | --- | --- | --- | --- |
|  | ACAM2000n=873 | Dryvax® n=289 |  | ACAM2000n=1371 | Dryvax® n=448 |
| 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
(<1%) |  | 9
(<1%) | 6
(1%) |

## Phase III DemographicsSafety Population

|  | H-400-009 
(Vaccinia-Naïve) |  |  | H-400-012 
(Previously Vaccinated) |  |
| --- | --- | --- | --- | --- | --- |
|  | ACAM2000n=873 | Dryvax® n=289 |  | ACAM2000n=1371 | Dryvax® n=448 |
| 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% |

## 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**

## Solicited Adverse Events Occurring in ≥10% of Subjects by Treatment Group, Phase III

|  | Vaccinia-Naïve |  |  | Previously Vaccinated |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| MedDRA Preferred Term | ACAM 2000
(n=873)
% | Dryvax®
(n=289)
% | p-value | ACAM 2000
(n=1371)
% | Dryvax®
(n=448)
% | p-value |
| At least 1 AE | 99 | 100 | 0.466 | 97 | 99 | 0.012 |
| Injection site pruritus | 92 | 96 | 0.032 | 82 | 93 | <0.001 |
| Injection site erythema | 74 | 79 | 0.098 | 61 | 72 | <0.001 |
| Injection site pain | 67 | 72 | 0.095 | 37 | 47 | <0.001 |
| Lymph node pain | 57 | 69 | <0.001 | 19 | 27 | <0.001 |
| 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 | <0.001 |
| 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 |

## Serious Adverse Events – All Studies

|  | Vaccinia-Naïve |  | Previously Vaccinated |  |
| --- | --- | --- | --- | --- |
|  | ACAM2000(n=1307) | Dryvax(n=368) | ACAM2000(n=1676) | Dryvax(n=500) |
| Deaths | 0 | 0 | 0 | 0 |
| At least 1 SAE | 13 (1%) | 4 (1%) | 6 (<1%) | 3 (1%) |
| Myocarditis / myopericarditis | 7 (0.54%) | 3 (0.82%) | 0 | 0 |
| Atrial fibrillation | 0 | 0 | 1 (<1%) | 0 |
| Coronary artery disease | 0 | 0 | 0 | 1 (<1%) |
| Chest discomfort | 0 | 0 | 1 (<1%) | 0 |
| Chest pain | 0 | 0 | 1 (<1%) | 0 |
| Hypersensitivity | 0 | 0 | 0 | 1 (<1%) |
| Appendicitis | 1 (<1%) | 0 | 1 (<1%) | 0 |
| Generalized vaccinia (‘cowpox’) | 0 | 0 | 0 | 1 (<1%) |
| HIV test positive subject vaccinated | 0 | 0 | 1(<1%) | 0 |
| Convulsions | 1 (<1%) | 0 | 0 | 0 |
| Pregnancy during on-study phase | 4 (<1%) | 0 | 1 (<1%) | 0 |
| Urticaria | 0 | 1 (<1%) | 0 | 0 |

**Notes:**
The percentages for myo/pericarditis are both <1

## 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**

## Myocarditis – Phase I (H-400-002) and Phase III (Vaccinia-naïve Subjects, Standardized Case Ascertainment)

|  | ACAM2000n=903 | Dryvax®n=319 |
| --- | --- | --- |
| 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 |

## Topics to be Covered

**Introduction**
**Nonclinical data**
**Clinical data**
**Safety**
**Efficacy**
**Conclusions**

## 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 >1:32)**
**Sarkar et al., 1975 (protective titer >1:20)**

## Phase III Trials Efficacy Analyses

| Co-Primary | Statistical Method | Secondary |
| --- | --- | --- |
| Cutaneous Response Rate | Non-inferiority 
Exclude margin of superiority of Dryvax® >5% (naïve) or >10% (prev. vacc.) | Covariate analyses (baseline immunity, H-400-012) |
| GMT | Non-inferiority
Ratio of ACAM2000:Dryvax® GMT at least 0.5      (log10  -0.301) | Covariate analyses (baseline immunity, H-400-012)
Titer freq. distribution
Fold-increase in PRNT
Seroconversion rates |

**Notes:**
Consider moving the entire Stats section to the beginning

## Phase III Endpoint: Cutaneous Response 

|  | Vaccinia-Naïve
(Study H-400-009) |  | Previously Vaccinated
(Study H-400-012) |  |
| --- | --- | --- | --- | --- |
|  | ACAM 2000
n=776 | Dryvax®
n=257 | ACAM 2000
n=1189 | Dryvax®
n=388 |
| Positive n (%) | 747 (96%) | 255 (99%) | 998 (84%) | 381 (98%) |
| 97.5% CI
(Criteria) | -4.67
(> -5.0%, lower bound of difference in rates) |  | -17
(> -10.0% , lower bound of difference in rates) |  |
| Non-inferiority 
Endpoint met? | Yes |  | No |  |

**ACAM2000 non-inferior to Dryvax****®**** in vaccinia-naïve subjects**
**ACAM2000 has lower cutaneous response rate than Dryvax****®**** in previously vaccinated subjects**

## Cutaneous Response RatesPreviously Vaccinated (Phase III), Adjusted for Baseline Antibody Titer (Antibody Evaluable Population)

**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****®**

| Baseline Titer | Statistic | Treatment Group |  |
| --- | --- | --- | --- |
|  |  | ACAM2000
(n=706) | Dryvax
(n=364) |
| <1:10 | Cutaneous Response | 151/161 (94%) | 86/88 (98%) |
| 1:10 – 1:20 |  | 158/186 (85%) | 107/108 (99%) |
| 1:40 – 1:80 |  | 168/199 (84%) | 93/94 (99%) |
| 1:160 |  | 116/160 (73%) | 72/74 (97%) |

**Notes:**
Not sure why the top line has been highlighted. Was there no statistical difference between vaccines in people with a baseline titre <1:10?

## Neutralizing Antibody Fold-IncreasePreviously Vaccinated (Phase III), Adjusted for Baseline Antibody Titer (Antibody Evaluable Population)

| Baseline Titer | Statistic | Treatment Group |  |
| --- | --- | --- | --- |
|  |  | ACAM2000
(n=706) | Dryvax
(n=364) |
| <1:10 | Fold-Increase (Geometric Mean Titer) | 29.6 | 36.4 |
| 1:10 – 1:20 |  | 13.3 | 23.8 |
| 1:40 – 1:80 |  | 5.9 | 10.9 |
| 1:160 |  | 2.2 | 4.8 |

## Phase III Endpoint: Neutralizing Antibody

|  | Vaccinia-Naïve
(Study H-400-009) |  | Previously Vaccinated
(Study H-400-012) |  |
| --- | --- | --- | --- | --- |
|  | ACAM 2000
n=565 | Dryvax®
n=190 | ACAM 2000
n=734 | Dryvax®
n=376 |
| GMT | 166 | 255 | 286 | 445 |
| 97.5% CI
(Criteria) | -0.307
(≥ -0.301*) |  | -0.275
(≥ -0.301*) |  |
| Non-inferiority 
Endpoint met? | No |  | Yes |  |
| * 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**

## >90% of Subjects Have Antibody Titers Greater than Historical Protective Level

**>90% of Subjects Have Antibody Titers Greater than Historical Protective Level**

## Categorical and Median T cell responsesNaïve Subjects (H-400-002)

## T cell (-IFN-ELISPOT) Responses (H-400-002)

**Positive response >20 spot-forming cells/10****6**

## 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**

## 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)**
**>90% with neutralizing antibody titers above putative protective level of 1:32**
**Narrowly missed statistical non-inferiority endpoint in naïve subjects (-.307 vs -.301)**
**Robust T cell responses similar to Dryvax****®**
**Important for immunological memory**

**Notes:**
Add “subjects” to second sub-bullet of bullet 4

## 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**
**>95% with neutralizing antibody titers above putative protective level of 1:32**
**Non-inferior to Dryvax****®**
**Cutaneous Response**
**84%, lower than Dryvax****®****, not non-inferior**
**94% in subjects without baseline antibody**

**Notes:**
Add “subjects” to second sub-bullet of bullet 4

## Mechanisms and Detection of Myocarditis andOutcomes 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*

## Topics

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

## Mechanism of Viral Myocarditis

## Triphasic Disease Process in Classic Myocarditis

**Autoimmune**
**Injury**

**Viral**
**Replication**

**Dilated Cardiomyopathy**

## Detection of Myocarditis

## 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**

## ACAM2000 Clinical Trials Myocarditis Case Summary

- ** Case not reviewed by CAP, but by Medical Monitor

**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 |

## 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 |

## Outcomes of Myocarditis

## Outcome in US Myocarditis Treatment Trial

## Incidence of Smallpox Vaccine-Related Myocarditis

## Incidence of “Myocarditis” Depends on Primary Diagnostic Criteria – Recent Experience Consistent with the Past 

| Source | Year | Vaccinees | Cases | Incidence | Resolution | Onset | Death |
| --- | --- | --- | --- | --- | --- | --- | --- |
| 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 | <26d | 3*** |
| CDC – Dryvax® | 2002 – 2007 | 40,449 | 21 | 0.05% | 3 Unresolved | <44d | 0 |
| 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 | <21d
 | 0 |
| ACAM2000 | 2003 – 2004 | 873 (P3)
2983 (all studies) | 5
7 | 0.57%
0.23% | All Resolved | <12d
<14d | 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

## Conclusions

**Incidence of smallpox vaccine-related myocarditis**
**Highly dependent on case ascertainment ****and definition**
**< 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**

## ACAM2000 Risk Management Plan (PVG Program & RiskMAP)

**Michael Watson, MD, PhD**
*Executive Vice President of **Research and Development*

## 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**

## 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**

## Elements of ACAM2000 PVG Program

|  | ACAM2000 
licensure |  | Year 1 |  | Year 2 |  | 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**

## 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**

## 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**

## Enhanced Surveillance (>100,000)

- Direct from subject, cards & email

- Potential signals/AEs of interest

- Cardiac events of interest

- Vaccination

- Symptom Solicitation at days 10 & 21

- Myocarditis Registry

- Adjudication Committee

## ACAM2000 Phase IV Trial (N=10,000+)

**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**

## 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**

## Phase IV Schedule of Events

- N=10,000+

- Vaccination

- Day 10Assessment

- Subject F/UScheduling(as required)

- Day 21Assessment

- Troponin,Symptoms

- Follow-Up forPossibleMyocarditis

**Other identified events**

**Follow-up**

**If**
**positive...**

**Screening, informed consent**

**Medical visit**

**Medical visit**

## 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**

## 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**

## Risk Minimization Action Plan(RiskMAP)

## Targets for Risk Minimization

**Potential vaccinees**
**Vaccinees**
**Contacts of vaccinees**
**Vaccinating physicians**
**Follow-up physicians**

## 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**

## Practical and Accessible Tools

**Practical and Accessible Tools**

## Auto-innoculation and Secondary Transmission

**Auto-innoculation and Secondary Transmission**

## 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 subject’s household**
**In light of recent case of EV, visibility and guidance will be further increased**

## Immuno-compromised

**Screening Form 600 currently used**
**Form records information regarding:**
**Subject’s immune system (e.g., immuno-deficiency due to cancer treatment, transplantation, AIDS, other conditions)**
**Subject’s HIV status**

## Inadvertent Use In Pregnancy

**Inadvertent Use In Pregnancy**

**Screening Form**
**Pregnancy Test**

## 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**

## 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**

## Encephalitis

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

## Compliance

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

## 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**

## 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**