Smallpox
Conditions
Keywords
IMVAMUNE®, smallpox, vaccine
Brief summary
The purpose of this study is to evaluate an investigational smallpox vaccine, called IMVAMUNE®, with respect to safety and immune (body's defense system) response. Participants will include healthy adults, age 18 or older born after 1971, who have not had smallpox vaccine before. Participants were originally assigned to 1 of 5 groups. In July 2007, a hold was placed on the Dryvax® groups and the study was modified. Participants, will be assigned by chance to one of 3 groups to be vaccinated twice with IMVAMUNE® vaccine or placebo (inactive substance) in Groups A and B, or to receive a single vaccination with IMVAMUNE® or placebo in Group F. Participants will complete a memory aid (diary) for 15 days following vaccination. Blood samples will be collected. Participants may participate for up to 425 days.
Detailed description
The study will evaluate the IMVAMUNE® smallpox vaccine with respect to safety and optimization of immune responses by different vaccination regimens in vaccinia-naïve adults. Study participants must be age 18 and older and born after 1971. Originally, participants were planned to be randomly assigned to 1 of 5 groups to be immunized twice with IMVAMUNE® vaccine or placebo subcutaneously in Groups A and B, or Dryvax® or placebo by scarification in Group C or both IMVAMUNE® and Dryvax® or 2 placebos in Groups D and Group E. In July 2007, enrollment was halted at the request of Center for Biologics Evaluation and Research (CBER). At that time, enrollment included zero subjects in Group A, 2 subjects in Group B, 8 subjects in Group C, 6 subjects in Group D, and 4 subjects in Group E. CBER placed an official hold on the enrollment into the Groups that would administer Dryvax®, i.e., Groups C, D and E. Subjects previously enrolled into Groups C, D, and E will be followed according to the protocol. The protocol has been modified as follows. Participants will be randomly assigned to 1 of 3 groups to be immunized twice with IMVAMUNE® vaccine or placebo subcutaneously in Groups A and B, or to receive a single immunization with IMVAMUNE® or placebo subcutaneously in Group F. (NOTE: Group B will contain two additional participants that were enrolled prior to modification.) Group A will receive IMVAMUNE® vaccine or placebo on Days 0 and 7. Group B will receive IMVAMUNE® vaccine or placebo on Days 0 and 28. Group F will receive a single dose of IMVAMUNE® at Day 0. All participants will complete a memory aid for 15 days following each vaccination. Groups C, D, and E will have the appropriate reactogenicity information collected until the vaccination lesion, if present is well dried. Adverse events will be collected for 28 days after each vaccination. Specimens will be collected for immunologic assays at the noted clinic visits, as well as 1 year post last vaccination. Serious adverse events will be collected throughout the study period. The primary safety objective is to evaluate the safety of IMVAMUNE® given as a single dose, IMVAMUNE® given in a 2 dose prime-boost regimen at Day 0 and 7 or Day 0 and 28, IMVAMUNE® followed by a boost with Dryvax®, and IMVAMUNE® given simultaneously with Dryvax®. The primary immunogenicity objective is to determine if the Geometric Mean Titer (GMT) of neutralizing antibody \[using Modified Vaccinia Ankara (MVA) as the target antigen\] among subjects receiving a regimen of 2 doses of IMVAMUNE® (1×10\^8, Days 0 and 7, Group A) is non-inferior to that among subjects receiving 2 doses of IMVAMUNE® (1×10\^8, Days 0 and 28, Group B) at Day 14 following the 2nd dose. The secondary immunogenicity objective is to determine if the GMT, as assessed by enzyme linked immunosorbent assay (ELISA) (using MVA as the target antigen), among subjects receiving a regimen of 2 doses of IMVAMUNE® (1×10\^8, Days 0 and 7, Group A) is non-inferior to that among subjects receiving 2 doses of IMVAMUNE® (1×10\^8, Days 0 and 28, Group B) at Day 14 following the 2nd dose. The tertiary immunogenicity objective is to characterize the kinetics, magnitude, and duration of cellular and humoral immune responses to IMVAMUNE® alone or IMVAMUNE® as a prime followed by a boost with IMVAMUNE® or Dryvax®, or Dryvax® alone.
Interventions
BIOLOGICALLive vaccinia virus vaccine
Dryvax® Vaccinia Vaccine (\ 10\^5 \[plaque forming units (pfu)/dose\] given via scarification, titer 10\^8 pfu per mL after reconstitution).
BIOLOGICALMVA Smallpox Vaccine
IMVAMUNE® Vaccinia Vaccine delivered by subcutaneous (SC) route at titer 1X10\^8 Tissue Culture Infections Dose50 per 0.5 mL dose.
OTHERPlacebo
0.9 percent (weight/volume) sodium chloride injection, United States Pharmacopeia \[Sterile Saline Placebo (SSP)\].
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 38 Years
Healthy volunteers
Yes
Inclusion criteria
-At least 18 years of age and born after 1971 -Never received smallpox vaccination -Read, signed, and dated informed consent document -Available for follow-up for the planned duration of the study (one year after last immunization) -Acceptable medical history by screening evaluation and limited physical assessment -If the subject is female and of childbearing potential, negative serum pregnancy test at screening and negative urine or serum pregnancy test within 24 hours prior to vaccination -If the subject is female and of childbearing potential, she agrees to use acceptable contraception, and not become pregnant for the duration of the study a. A woman is considered of childbearing potential unless post-menopausal or surgically sterilized b. Acceptable contraception methods are restricted to effective devices (e.g., Intrauterine Devices (IUD)s, NuvaRing®) or licensed hormonal products with use of method for a minimum of 30 days prior to vaccination, and abstinence from sexual intercourse with men (vaginal penetration by a penis, coitus) c. Women who are not sexually active must agree to use one of the acceptable contraception methods if they are of childbearing potential -Negative enzyme linked immunosorbent assay (ELISA) for human immunodeficiency virus (HIV) -Alanine aminotransferase (ALT) \<1.25 times institutional upper limit of normal -Negative hepatitis B surface antigen and negative antibody to hepatitis C virus -Negative urine glucose and urine protein \<1 plus by dipstick or urinalysis Adequate renal function defined as a serum creatinine equal to or less than the institutional upper limit of normal by gender; and urine protein \<30 mg/dL or trace proteinuria (by urinalysis or dip stick). -Electrocardiogram (ECG) in absence of clinical significance (e.g., complete left or right bundle branch block, incomplete left bundle branch block or sustained ventricular arrythmia, or two premature ventricular contractions (PVC's) in a row, or sympathetic tonus (ST) elevation consistent with ischemia) -Complete blood count (CBC): Hemoglobin equal to or above the lower limit of institutional normal; White blood cells greater than or equal to 3200 /mm\^3 and equal to or below the upper limit of institutional normal Platelets equal to or above the lower limit of institutional normal -Weight: greater than or equal to 110 pounds
Exclusion criteria
-History of immunodeficiency -Typical vaccinia scar -Known or suspected history of smallpox vaccination -Military service prior to 1991 or after January 2003 -Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease, diabetes mellitus, or moderate to severe kidney impairment -Malignancy not including squamous cell skin cancer or basal cell skin cancer unless at the vaccination site or history of skin cancer at the vaccination site -Active autoimmune disease Persons with vitiligo or thyroid disease (e.g., taking thyroid hormone replacement) are not excluded. -History of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, or other heart condition under the care of a doctor -Ten percent or greater risk of developing a myocardial infarction or coronary death within the next 10 years using the National Cholesterol Education Program's risk assessment tool (http://hin.nhlbi.nih.gov/atpiii/calculator.asp) -NOTE that this criterion applies only to subjects 20 years of age and older AND only if at least one of the following apply: a. have smoked a cigarette in the past month, and/or b. have hypertension (defined as systolic blood pressure \>140 mm Hg) or are on antihypertensive medication, and/or c. have a family history of coronary heart disease in male first-degree relative (father or brother) \<55 years of age or a female first-degree relative (mother or sister) \<65 years of age. -Current use of immunosuppressive medication a. Corticosteroid nasal sprays are permissible b. Persons who are using a topical steroid can be enrolled after their therapy is completed c. Inhaled steroids for asthma are not permissible -Medical or psychiatric condition or occupational responsibilities that preclude subject compliance with the protocol -Any history of illegal injection drug use -Receipt of inactivated vaccine 14 days prior to vaccination -Receipt of live attenuated vaccine within 30 days prior to vaccination -Use of experimental agent within 30 days prior to vaccination -Receipt of blood products or immunoglobulin within six months prior to vaccination -Donation of a unit of blood within 56 days prior to vaccination or for the duration of the study -Acute febrile illness (greater than or equal to 100.5 degrees F) on the day of vaccination -Pregnant or lactating women -Eczema of any degree or history of eczema -People with atopic dermatitis, chronic exfoliative skin disorders/conditions, current Varicella zoster, or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2×2 cm -Any condition that, in the opinion of the investigator, might interfere with study objectives -Known allergy to IMVAMUNE® vaccine -Known allergy to egg or aminoglycoside -Study personnel
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Systemic Solicited Reactogenicity AEs for Groups C, E, and F and Placebo E and F | Day 0 through Day 15 after first vaccination | Systemic solicited reactogenicity AEs were collected daily for 15 days post vaccination using a memory aid. Systemic events included muscle aches, chills, headache, nausea, feeling tired, change in appetite, joint pain, and elevated oral temperature. Events were graded on a subjective scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe). |
| Frequency of Local Solicited Reactogenicity AEs for Group E and Placebo E | Day 0 through Day 15 after first vaccination | Local solicited reactogenicity AEs were collected daily for 15 days post vaccination using a memory aid. Results are reported by vaccination site (MVA Vaccination or Dryvax Vaccination). Local events included pain at vaccination site, itchiness at vaccination site, rash at vaccination site underarm pain, underarm swelling, erythema, and induration. Erythema and induration at the vaccination site were measured in millimeters; the remaining events were graded on a subjective scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe). |
| Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Day 0 through Day 15 after first vaccination; Day 0 through Day 15 after second vaccination | Systemic solicited reactogenicity AEs were collected daily for 15 days post each vaccination using a memory aid. Systemic events included muscle aches, chills, headache, nausea, feeling tired, change in appetite, joint pain, and elevated oral temperature. Events were graded on a subjective scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe). |
| Frequency of Non-Serious AEs | Day 0 after first vaccination through Day 28 after last vaccination | The number of participants who experienced at least one unsolicited non-serious AE of any severity from Day 0 after the first vaccination to 28 days after the last vaccination. |
| Geometric Mean Titer (GMT) of Bavarian Nordic's (BN) Plaque Reduction Neutralizing Antibody Titer (PRNT) Assay in Groups A and B | Day 14 after the second vaccination | Geometric mean of titers collected 14 days after the second vaccination. |
| GMT of Saint Louis University's (SLU) PRNT Assay in Group A and Group B | Day 14 after the second vaccination | Geometric mean of titers collected 14 days after the second vaccination. |
| Frequency of Serious Adverse Events (SAEs) | Day 0 after first vaccination to study completion through Day 365 after last vaccination | The number of participants who experienced at least one SAE throughout the course of the study. A SAE is defined as an AE meeting one of the following conditions: * Death during the study period (from first vaccine until end of surveillance period) * Life-threatening (defined as a participant at immediate risk of death at the time of the event) * Requires inpatient hospitalization or prolongation of existing hospitalization during the period of protocol-defined surveillance * Results in a congenital anomaly or birth defect * Results in a persistent or significant disability/incapacity * Severe adverse event associated with study product |
| Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Day 0 through Day 15 after first vaccination; Day 0 through Day 15 after second vaccination | Local solicited reactogenicity AEs were collected daily for 15 days post each vaccination using a memory aid. Local events include pain at vaccination site, itchiness at vaccination site, rash at vaccination site underarm pain, underarm swelling, erythema, and induration. Erythema and induration at the vaccination site were measured in millimeters; the remaining events were graded on a subjective scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe). |
| Frequency of Local Solicited Reactogenicity AEs for Groups C and F and Placebo F | Day 0 through Day 15 after first vaccination | Local solicited reactogenicity AEs were collected daily for 15 days post vaccination using a memory aid. Local events include pain at vaccination site, itchiness at vaccination site, rash at vaccination site underarm pain, underarm swelling, erythema, and induration. Erythema and induration at the vaccination site were measured in millimeters; the remaining events were graded on a subjective scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GMT of SLU ELISA in Groups A and B | Day 14 after the second vaccination | Geometric mean of titers collected 14 days after the second vaccination. |
| GMT of BN Enzyme Linked Immunosorbent Assay (ELISA) in Groups A and B | Day 14 after the second vaccination | Geometric mean of titers collected 14 days after the second vaccination. |
Countries
United States
Participant flow
Recruitment details
The study population included adults aged greater than 18 years (and born after 1971) who met all inclusion/exclusion criteria. Participants were recruited from seven sites within the United States. The first participant was enrolled on April 16, 2007, and the last participant was enrolled on April 3, 2008.
Participants by arm
| Arm | Count |
|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 Standard dose IMVAMUNE® vaccine on Days 0 and 7. | 61 |
| Group B: Two Doses IMVAMUNE, Days 0, 28 Standard dose IMVAMUNE® vaccine on Days 0 and 28. | 66 |
| Group C: One Dose Dryvax, Day 0 Dryvax® vaccine on Day 0. This arm was discontinued from original protocol. Participants already enrolled in this group continued follow-up per protocol. | 8 |
| Group D: IMVAMUNE, Day 0 + Dryvax, Day 7 Standard dose IMVAMUNE® vaccine on Day 0 and Dryvax® vaccine on Day 7. This arm was discontinued from original protocol. Participants already enrolled in this group continued follow-up per protocol. | 5 |
| Group E: IMVAMUNE + Dryvax, Day 0 Dryvax® vaccine and standard dose IMVAMUNE® vaccine on Day 0. This arm was discontinued from original protocol. Participants already enrolled in this group continued follow-up per protocol. | 2 |
| Group F: IMVAMUNE, Day 0 Standard dose IMVAMUNE® vaccine on Day 0. | 63 |
| Placebo A Placebo participants from Group A. Placebo administered corresponding to method for active drug administration in Group A. | 6 |
| Placebo B Placebo participants from Group B. Placebo administered corresponding to method for active drug administration in Group B. | 5 |
| Placebo D Placebo participants from Group D. Placebo administered corresponding to method for active drug administration in Group D. | 1 |
| Placebo E Placebo participants from Group E. Placebo administered corresponding to method for active drug administration in Group E. | 2 |
| Placebo F Placebo participants from Group F. Placebo administered corresponding to method for active drug administration in Group F. | 7 |
| Total | 226 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 3 | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Group B: Two Doses IMVAMUNE, Days 0, 28 | Group C: One Dose Dryvax, Day 0 | Group A: Two Doses IMVAMUNE, Days 0, 7 | Group D: IMVAMUNE, Day 0 + Dryvax, Day 7 | Group E: IMVAMUNE + Dryvax, Day 0 | Group F: IMVAMUNE, Day 0 | Placebo A | Placebo B | Placebo D | Placebo E | Placebo F | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 25.0 years STANDARD_DEVIATION 3.9 | 26.5 years STANDARD_DEVIATION 4.3 | 24.7 years STANDARD_DEVIATION 4.6 | 26.4 years STANDARD_DEVIATION 5.1 | 31.0 years STANDARD_DEVIATION 4.2 | 24.3 years STANDARD_DEVIATION 3.9 | 25.2 years STANDARD_DEVIATION 3.5 | 21.4 years STANDARD_DEVIATION 2.3 | 24.0 years | 20.5 years STANDARD_DEVIATION 0.7 | 27.9 years STANDARD_DEVIATION 4.8 | 24.8 years STANDARD_DEVIATION 4.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 8 Participants | 59 Participants | 5 Participants | 2 Participants | 60 Participants | 5 Participants | 5 Participants | 1 Participants | 2 Participants | 7 Participants | 217 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 0 Participants | 5 Participants | 1 Participants | 0 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 56 Participants | 8 Participants | 52 Participants | 4 Participants | 2 Participants | 54 Participants | 6 Participants | 4 Participants | 1 Participants | 2 Participants | 6 Participants | 195 Participants |
| Sex: Female, Male Female | 36 Participants | 1 Participants | 25 Participants | 2 Participants | 1 Participants | 32 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 105 Participants |
| Sex: Female, Male Male | 30 Participants | 7 Participants | 36 Participants | 3 Participants | 1 Participants | 31 Participants | 3 Participants | 5 Participants | 1 Participants | 2 Participants | 2 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 67 | 0 / 8 | 0 / 5 | 0 / 2 | 0 / 63 | 0 / 6 | 0 / 4 | 0 / 1 | 0 / 2 | 0 / 7 |
| other Total, other adverse events | 57 / 61 | 66 / 67 | 8 / 8 | 5 / 5 | 2 / 2 | 58 / 63 | 6 / 6 | 4 / 4 | 1 / 1 | 2 / 2 | 6 / 7 |
| serious Total, serious adverse events | 1 / 61 | 2 / 67 | 0 / 8 | 0 / 5 | 0 / 2 | 3 / 63 | 0 / 6 | 0 / 4 | 0 / 1 | 0 / 2 | 0 / 7 |
Outcome results
Primary
Frequency of Local Solicited Reactogenicity AEs for Group E and Placebo E
Local solicited reactogenicity AEs were collected daily for 15 days post vaccination using a memory aid. Results are reported by vaccination site (MVA Vaccination or Dryvax Vaccination). Local events included pain at vaccination site, itchiness at vaccination site, rash at vaccination site underarm pain, underarm swelling, erythema, and induration. Erythema and induration at the vaccination site were measured in millimeters; the remaining events were graded on a subjective scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe).
Time frame: Day 0 through Day 15 after first vaccination
Population: The safety population includes all participants who received one dose of vaccine. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Frequency of Local Solicited Reactogenicity AEs for Group E and Placebo E | MVA Vaccination | 1 Participants |
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Frequency of Local Solicited Reactogenicity AEs for Group E and Placebo E | Dryvax Vaccination | 2 Participants |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Frequency of Local Solicited Reactogenicity AEs for Group E and Placebo E | MVA Vaccination | 0 Participants |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Frequency of Local Solicited Reactogenicity AEs for Group E and Placebo E | Dryvax Vaccination | 2 Participants |
Primary
Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D
Local solicited reactogenicity AEs were collected daily for 15 days post each vaccination using a memory aid. Local events include pain at vaccination site, itchiness at vaccination site, rash at vaccination site underarm pain, underarm swelling, erythema, and induration. Erythema and induration at the vaccination site were measured in millimeters; the remaining events were graded on a subjective scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe).
Time frame: Day 0 through Day 15 after first vaccination; Day 0 through Day 15 after second vaccination
Population: The safety population includes all participants who received one dose of vaccine. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 47 Participants |
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 51 Participants |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 50 Participants |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 53 Participants |
| Group C: One Dose Dryvax, Day 0 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 4 Participants |
| Group C: One Dose Dryvax, Day 0 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 3 Participants |
| Group D: IMVAMUNE, Day 0 + Dryvax, Day 7 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 1 Participants |
| Group D: IMVAMUNE, Day 0 + Dryvax, Day 7 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 0 Participants |
| Group E: IMVAMUNE + Dryvax, Day 0 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 2 Participants |
| Group E: IMVAMUNE + Dryvax, Day 0 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 0 Participants |
| Group F: IMVAMUNE, Day 0 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 0 Participants |
| Group F: IMVAMUNE, Day 0 | Frequency of Local Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 1 Participants |
Primary
Frequency of Local Solicited Reactogenicity AEs for Groups C and F and Placebo F
Local solicited reactogenicity AEs were collected daily for 15 days post vaccination using a memory aid. Local events include pain at vaccination site, itchiness at vaccination site, rash at vaccination site underarm pain, underarm swelling, erythema, and induration. Erythema and induration at the vaccination site were measured in millimeters; the remaining events were graded on a subjective scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe).
Time frame: Day 0 through Day 15 after first vaccination
Population: The safety population includes all participants who received one dose of vaccine. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Frequency of Local Solicited Reactogenicity AEs for Groups C and F and Placebo F | 8 Participants |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Frequency of Local Solicited Reactogenicity AEs for Groups C and F and Placebo F | 50 Participants |
| Group C: One Dose Dryvax, Day 0 | Frequency of Local Solicited Reactogenicity AEs for Groups C and F and Placebo F | 1 Participants |
Primary
Frequency of Non-Serious AEs
The number of participants who experienced at least one unsolicited non-serious AE of any severity from Day 0 after the first vaccination to 28 days after the last vaccination.
Time frame: Day 0 after first vaccination through Day 28 after last vaccination
Population: The safety population includes all participants who received one dose of vaccine. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Frequency of Non-Serious AEs | 32 Participants |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Frequency of Non-Serious AEs | 43 Participants |
| Group C: One Dose Dryvax, Day 0 | Frequency of Non-Serious AEs | 4 Participants |
| Group D: IMVAMUNE, Day 0 + Dryvax, Day 7 | Frequency of Non-Serious AEs | 1 Participants |
| Group E: IMVAMUNE + Dryvax, Day 0 | Frequency of Non-Serious AEs | 0 Participants |
| Group F: IMVAMUNE, Day 0 | Frequency of Non-Serious AEs | 26 Participants |
| Placebo A | Frequency of Non-Serious AEs | 4 Participants |
| Placebo B | Frequency of Non-Serious AEs | 2 Participants |
| Placebo D | Frequency of Non-Serious AEs | 0 Participants |
| Placebo E | Frequency of Non-Serious AEs | 0 Participants |
| Placebo F | Frequency of Non-Serious AEs | 5 Participants |
Primary
Frequency of Serious Adverse Events (SAEs)
The number of participants who experienced at least one SAE throughout the course of the study. A SAE is defined as an AE meeting one of the following conditions: * Death during the study period (from first vaccine until end of surveillance period) * Life-threatening (defined as a participant at immediate risk of death at the time of the event) * Requires inpatient hospitalization or prolongation of existing hospitalization during the period of protocol-defined surveillance * Results in a congenital anomaly or birth defect * Results in a persistent or significant disability/incapacity * Severe adverse event associated with study product
Time frame: Day 0 after first vaccination to study completion through Day 365 after last vaccination
Population: The safety population includes all participants who received one dose of vaccine. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Frequency of Serious Adverse Events (SAEs) | 1 Participants |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Frequency of Serious Adverse Events (SAEs) | 2 Participants |
| Group C: One Dose Dryvax, Day 0 | Frequency of Serious Adverse Events (SAEs) | 0 Participants |
| Group D: IMVAMUNE, Day 0 + Dryvax, Day 7 | Frequency of Serious Adverse Events (SAEs) | 0 Participants |
| Group E: IMVAMUNE + Dryvax, Day 0 | Frequency of Serious Adverse Events (SAEs) | 0 Participants |
| Group F: IMVAMUNE, Day 0 | Frequency of Serious Adverse Events (SAEs) | 3 Participants |
| Placebo A | Frequency of Serious Adverse Events (SAEs) | 0 Participants |
| Placebo B | Frequency of Serious Adverse Events (SAEs) | 0 Participants |
| Placebo D | Frequency of Serious Adverse Events (SAEs) | 0 Participants |
| Placebo E | Frequency of Serious Adverse Events (SAEs) | 0 Participants |
| Placebo F | Frequency of Serious Adverse Events (SAEs) | 0 Participants |
Primary
Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D
Systemic solicited reactogenicity AEs were collected daily for 15 days post each vaccination using a memory aid. Systemic events included muscle aches, chills, headache, nausea, feeling tired, change in appetite, joint pain, and elevated oral temperature. Events were graded on a subjective scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe).
Time frame: Day 0 through Day 15 after first vaccination; Day 0 through Day 15 after second vaccination
Population: The safety population includes all participants who received one dose of vaccine. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 31 Participants |
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 29 Participants |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 41 Participants |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 23 Participants |
| Group C: One Dose Dryvax, Day 0 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 2 Participants |
| Group C: One Dose Dryvax, Day 0 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 3 Participants |
| Group D: IMVAMUNE, Day 0 + Dryvax, Day 7 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 4 Participants |
| Group D: IMVAMUNE, Day 0 + Dryvax, Day 7 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 2 Participants |
| Group E: IMVAMUNE + Dryvax, Day 0 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 3 Participants |
| Group E: IMVAMUNE + Dryvax, Day 0 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 3 Participants |
| Group F: IMVAMUNE, Day 0 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post First Vaccination | 0 Participants |
| Group F: IMVAMUNE, Day 0 | Frequency of Systemic Solicited Reactogenicity AEs for Groups A, B, and D and Placebo A, B, and D | Post Second Vaccination | 0 Participants |
Primary
Frequency of Systemic Solicited Reactogenicity AEs for Groups C, E, and F and Placebo E and F
Systemic solicited reactogenicity AEs were collected daily for 15 days post vaccination using a memory aid. Systemic events included muscle aches, chills, headache, nausea, feeling tired, change in appetite, joint pain, and elevated oral temperature. Events were graded on a subjective scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe).
Time frame: Day 0 through Day 15 after first vaccination
Population: The safety population includes all participants who received one dose of vaccine. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Frequency of Systemic Solicited Reactogenicity AEs for Groups C, E, and F and Placebo E and F | 5 Participants |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Frequency of Systemic Solicited Reactogenicity AEs for Groups C, E, and F and Placebo E and F | 2 Participants |
| Group C: One Dose Dryvax, Day 0 | Frequency of Systemic Solicited Reactogenicity AEs for Groups C, E, and F and Placebo E and F | 33 Participants |
| Group D: IMVAMUNE, Day 0 + Dryvax, Day 7 | Frequency of Systemic Solicited Reactogenicity AEs for Groups C, E, and F and Placebo E and F | 1 Participants |
| Group E: IMVAMUNE + Dryvax, Day 0 | Frequency of Systemic Solicited Reactogenicity AEs for Groups C, E, and F and Placebo E and F | 3 Participants |
Primary
Geometric Mean Titer (GMT) of Bavarian Nordic's (BN) Plaque Reduction Neutralizing Antibody Titer (PRNT) Assay in Groups A and B
Geometric mean of titers collected 14 days after the second vaccination.
Time frame: Day 14 after the second vaccination
Population: The analysis population includes all participants who received two doses of study vaccine and contributed both pre- and post-vaccination blood samples for testing for which valid results were reported. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | Geometric Mean Titer (GMT) of Bavarian Nordic's (BN) Plaque Reduction Neutralizing Antibody Titer (PRNT) Assay in Groups A and B | 10.8 titer |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | Geometric Mean Titer (GMT) of Bavarian Nordic's (BN) Plaque Reduction Neutralizing Antibody Titer (PRNT) Assay in Groups A and B | 30.2 titer |
Comparison: Null hypothesis: The mean difference in log2 transformed titers between Group B and Group A \>= 1.95% CI: [0.97, 1.99]
Primary
GMT of Saint Louis University's (SLU) PRNT Assay in Group A and Group B
Geometric mean of titers collected 14 days after the second vaccination.
Time frame: Day 14 after the second vaccination
Population: The analysis population includes all participants who received two doses of study vaccine and contributed both pre- and post-vaccination blood samples for testing for which valid results were reported. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | GMT of Saint Louis University's (SLU) PRNT Assay in Group A and Group B | 27.4 titer |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | GMT of Saint Louis University's (SLU) PRNT Assay in Group A and Group B | 212.2 titer |
Comparison: Null hypothesis: The mean difference in log2 transformed titers between Group B and Group A \>= 1.95% CI: [2.22, 3.69]
Secondary
GMT of BN Enzyme Linked Immunosorbent Assay (ELISA) in Groups A and B
Geometric mean of titers collected 14 days after the second vaccination.
Time frame: Day 14 after the second vaccination
Population: The analysis population includes all participants who received two doses of study vaccine and contributed both pre- and post-vaccination blood samples for testing for which valid results were reported. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | GMT of BN Enzyme Linked Immunosorbent Assay (ELISA) in Groups A and B | 108.7 titer |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | GMT of BN Enzyme Linked Immunosorbent Assay (ELISA) in Groups A and B | 501.7 titer |
Comparison: Null hypothesis: The mean difference in log2 transformed titers between Group B and Group A \>= 1.95% CI: [1.65, 2.76]
Secondary
GMT of SLU ELISA in Groups A and B
Geometric mean of titers collected 14 days after the second vaccination.
Time frame: Day 14 after the second vaccination
Population: The analysis population includes all participants who received two doses of study vaccine and contributed both pre- and post-vaccination blood samples for testing for which valid results were reported. Participants were analyzed as treated according to the study product they received.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Group A: Two Doses IMVAMUNE, Days 0, 7 | GMT of SLU ELISA in Groups A and B | 60.5 titer |
| Group B: Two Doses IMVAMUNE, Days 0, 28 | GMT of SLU ELISA in Groups A and B | 510.9 titer |
Comparison: Null hypothesis: The mean difference in log2 transformed titers between Group B and Group A \>= 1.95% CI: [2.57, 3.59]