Smallpox
Conditions
Keywords
IMVAMUNE®, smallpox, vaccine
Brief summary
Due to recent concern of biowarfare and bioterrorism, the US government is making efforts to improve its ability to protect citizens against the smallpox virus. This study will evaluate safety of IMVAMUNE®, an investigational smallpox vaccine, and its ability to stimulate the immune system (the body's defense system). Two vaccine preparations have the same name but one is a liquid and one is a powder that has liquid added just before it is given. The vaccine that comes as a liquid will be injected (given as a shot) just under the skin (subcutaneously) or injected between the layers of the skin (intradermally). The powder formulation is only injected just under the skin. Approximately 495 adults, age 18 older born after 1971, which have not had smallpox vaccine before, may participate in the study for about 7 months.
Detailed description
Smallpox was declared officially eradicated by the World Health Assembly in 1980. Despite the fact that the World Health Organization (WHO) officially declared smallpox to be eradicated, a new threat exists due to the potential use of variola virus as an agent for biological warfare and/or bio-terrorism. Following the events of September 11, 2001 the Division of Microbiology and Infectious Diseases/National Institute of Allergy and Infectious Diseases contracted for the advanced development of IMVAMUNE®. Initially, a lyophilized formulation was manufactured, which was reconstituted 'at the bedside' prior to administration in clinical and non-clinical settings. Due in part to the potential requirement for mass vaccinations coupled with the increased manufacturing time and other constrains associated with lyophilization, it was decided to transition to a liquid product formulation. Therefore, after 2005, clinical and non-clinical efforts have focused largely on the liquid formulation, though non-clinical studies with the lyophilized formulation continued. Presently, due to the potential need to be able to stockpile Modified Vaccinia Ankara (MVA) for an extended period of time, there is renewed interest in the lyophilized formulation. The purpose of this study is to compare the safety and immunogenicity of lyophilized IMVAMUNE® \[1x10\^8 tissue culture infectious dose 50 (TCID50)\] versus liquid formulation IMVAMUNE® (1x10\^8 TCID50) administered by the subcutaneous (SC) route and a lower dose liquid formulation IMVAMUNE® (2x10\^7 TCID50) administered by the intradermal (ID) route in healthy vaccinia-naïve individuals. This study is designed as a randomized, non-placebo controlled, partially-blinded study (liquid versus lyophilized formulation by the SC route Group B versus A). The study staff is unblinded to Group C. The study will contain 3 arms: Group A \[Number (N)=165\] will receive a 2 dose regimen of IMVAMUNE® (1x10\^8 TCID50/0.5 mL per dose) lyophilized formulation by the SC route on Day 0 and 28. Group B (N=165) will receive a 2 dose regimen of IMVAMUNE® (1x10\^8 TCID50/0.5 mL per dose) liquid formulation by the SC route on Day 0 and 28. Group C (N=165) will receive a 2 dose regimen of IMVAMUNE® (2x10\^7 TCID50/0.1 mL per dose) liquid formulation by the ID route on Day 0 and 28. Safety will be measured by assessment of solicited local and systemic reactions within 15 days after each vaccination (Day 0-14), unsolicited adverse events for 28 days following the second vaccination (56 days following the initial vaccination for those subjects that fail to receive the second vaccination), and serious adverse events through six months post the final vaccination. Immunogenicity testing will include assessment of vaccinia-specific plaque reduction neutralizing antibody titers (PRNT) and enzyme linked immunosorbent assay (ELISA) mean geometric titers (GMT) based on individual peak titers. For each subject, the peak PRNT or ELISA will be defined as the largest titer among all available measurements post second vaccination.
Interventions
BIOLOGICALMVA Smallpox Vaccine
Vaccinia vaccine liquid formulation delivered by subcutaneous (SC) route at 1x10\^8 TCID50 per 0.5 mL dose on Days 0 and 28.
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
Inclusion criteria that must be met prior to the initial vaccination: * At least 18 years of age and born after 1971. * Read, signed, and dated informed consent document. * Available for follow-up for the planned duration of the study (6 months 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 28 days following the last vaccination: 1. A woman is considered of childbearing potential unless post-menopausal (greater than or equal to 1 year) or surgically sterilized (tubal ligation, bilateral oophorectomy, or hysterectomy). 2. Acceptable contraception methods are restricted to effective devices \[intrauterine devices (IUD)s, NuvaRing®\] or licensed hormonal products with use of method for a minimum of 30 days prior to vaccination, abstinence from sexual intercourse with men (vaginal penetration by a penis, coitus), and monogamous relationship with a vasectomized partner. * 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 is defined as a serum creatinine not exceeding the institution's upper limit of normal. * Electrocardiogram (ECG) in absence of clinical significance (e.g., complete left or right bundle branch block, incomplete left bundle branch block or sustained ventricular arrhythmia, or 2 premature ventricular contraction's (PVC)'s in a row, or sympathetic tonus (ST) elevation consistent with ischemia). * The following blood parameters: 1. Hemoglobin equal or above the lower limit of institutional normal (sex-specific); 2. White blood cells greater than 2,500 and less than 11,000/mm\^3; 3. Platelets greater than or equal to 140,000/mm\^3. * Weight: greater than or equal to 110 pounds. Inclusion Criteria that must be met prior to the second vaccination: * Acceptable medical history. * If the subject is female and of childbearing potential, 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 28 days following the last vaccination: 1. A woman is considered of childbearing potential unless post-menopausal (greater than or equal to 1 year) or surgically sterilized (tubal ligation, bilateral oophorectomy, or hysterectomy). 2. Acceptable contraception methods are restricted to effective devices (IUDs, NuvaRing®) or licensed hormonal products with use of method for a minimum of 30 days prior to vaccination, abstinence from sexual intercourse with men (vaginal penetration by a penis, coitus), and monogamous relationship with a vasectomized partner.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Serious Adverse Events Associated With IMVAMUNE® Vaccination | Day 0 through 180 days after second vaccination | An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Those SAEs considered associated are those with a known temporal relationship, or the event is known to occur in association with study product or with a product in a similar class of study products AND no alternate etiology is identified. |
| Geometric Mean Titer (GMT) Based on Vaccinia-specific Individual Peak Plaque Reduction Neutralization Titers (PRNT) Following 2 Doses of IMVAMUNE® Lyophilized Versus Following 2 Doses of IMVAMUNE® Liquid Administered Subcutaneously, ITT Population | Days 14, 28 and 180 after 2nd vaccination | Blood was collected from participants for testing in the PRNT assay with vaccinia-Western Reserve (replicating vaccinia) as the assay antigen. The geometric mean titers were calculated for each participant's individual peak titer after second vaccination. Titer values below limit of detection were replaced by 7.5 (half the lower limit of detection) for analysis. |
| GMT Based on Vaccinia-specific Individual Peak PRNT Following 2 Doses of IMVAMUNE® Lyophilized Versus Following 2 Doses of IMVAMUNE® Liquid Administered Subcutaneously, Per Protocol Population | Days 14, 28 and 180 after 2nd vaccination | Blood was collected from participants for testing in the PRNT assay with vaccinia-Western Reserve (replicating vaccinia) as the assay antigen. The geometric mean titers were calculated for each participant's individual peak titer after second vaccination. Titer values below limit of detection were replaced by 7.5 (half the lower limit of detection) for analysis. |
| GMT Based on Vaccinia-specific Individual Peak PRNT, Following 2 (Lower) Doses Liquid IMVAMUNE® Administered Intradermally Versus 2 (Higher) Doses of Liquid IMVAMUNE® Administered Subcutaneously, ITT Population | Days 14, 28 and 180 after 2nd vaccination | Blood was collected from participants for testing in the PRNT assay with vaccinia-Western Reserve (replicating vaccinia) as the assay antigen. The geometric mean titers were calculated for each participant's individual peak titer after second vaccination. Titer values below limit of detection were replaced by 7.5 (half the lower limit of detection) for analysis. |
| GMT Based on Vaccinia-specific Individual Peak PRNT, Following 2 (Lower) Doses Liquid IMVAMUNE® Administered Intradermally Versus 2 (Higher) Doses of Liquid IMVAMUNE® Administered Subcutaneously, Per Protocol Population | Days 14, 28 and 180 after 2nd vaccination | Blood was collected from participants for testing in the PRNT assay with vaccinia-Western Reserve (replicating vaccinia) as the assay antigen. The geometric mean titers were calculated for each timepoint as well as for the peak titer after second vaccination. Titer values below limit of detection were replaced by 7.5 (half the lower limit of detection) for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Assessed With Grade 3 and 4 Laboratory Toxicities Associated With IMVAMUNE®. | Days 0, 14 and 42 | Safety laboratory parameters included hemoglobin, white blood cells (WBC), platelets, ALT, and serum creatinine. These parameters were evaluated at Day 0 and 14 days after vaccination. Thresholds for Grade 3 or 4 were hemoglobin less than 8.0 g/dL, WBC less than 2000 cells/mm\^3, platelets less than 50,000 cells/mm\^3, ALT 5.0 times the upper limit of normal (ULN) or greater, and serum creatinine of 1.9 times ULN or greater. Associated with IMVAMUNE was defined as a known temporal relationship, or the event is known to occur in association with study product or with a product in a similar class of study products AND no alternate etiology is identified. |
| GMT Based on Vaccinia-specific Individual Peak ELISA Titers, Following 2 Doses (Lower) Liquid Formulation IMVAMUNE® Administered Intradermally Versus That Obtained Following 2 Doses IMVAMUNE® Liquid Formulation Administered Subcutaneously, ITT Population | Days 14, 28 and 180 after 2nd vaccination | Blood was collected from participants for testing in the ELISA assay with IMVAMUNE (non-replicating vaccinia in humans) as the assay antigen. The geometric mean titers were calculated for each participant's individual peak titer after second vaccination. Titer values below limit of detection were replaced by 25 (half the lower limit of detection) for analysis. |
| GMT Based on Vaccinia-specific Individual Peak ELISA Titers, Following 2 Doses (Lower) Liquid Formulation IMVAMUNE® Administered Intradermally Versus That Obtained Following 2 Doses IMVAMUNE® Liquid Formulation Subcutaneously, Per Protocol Population | Days 14, 28 and 180 after second vaccination | Blood was collected from participants for testing in the ELISA assay with IMVAMUNE (non-replicating vaccinia in humans) as the assay antigen. The geometric mean titers were calculated for each participant's individual peak titer after second vaccination. Titer values below limit of detection were replaced by 25 (half the lower limit of detection) for analysis. |
| GMT Based on Vaccinia-specific Individual Peak ELISA Titers Following 2 Doses of IMVAMUNE® Lyophilized Formulation Versus That Obtained Following 2 Doses of IMVAMUNE® Liquid Formulation Subcutaneously, ITT Population. | Days 14, 28 and 180 after 2nd vaccination. | Blood was collected from participants for testing in the ELISA assay with IMVAMUNE (non-replicating vaccinia in humans) as the assay antigen. The geometric mean titers were calculated using the individual peak titer after second vaccination. Titer values below limit of detection were replaced by 25 (half the lower limit of detection) for analysis. |
| GMT Based on Vaccinia-specific Individual Peak ELISA Titers Following 2 Doses of IMVAMUNE® Lyophilized Formulation Versus That Obtained Following 2 Doses of IMVAMUNE® Liquid Formulation Subcutaneously, Per Protocol Population. | Days 14, 28 and 180 after 2nd vaccination. | Blood was collected from participants for testing in the ELISA assay with IMVAMUNE (non-replicating vaccinia in humans) as the assay antigen. The geometric mean titers were calculated using the individual peak titer after second vaccination. Titer values below limit of detection were replaced by 25 (half the lower limit of detection) for analysis. |
Countries
United States
Participant flow
Recruitment details
Participants were healthy adults age 18 and older (born after 1971) recruited from existing volunteer populations and from the communities at large around the clinical sites. Participants were enrolled between 09FEB2010 and 02SEP2010.
Participants by arm
| Arm | Count |
|---|---|
| Lyophilized, Subcutaneous Participants receive a 2 dose regimen of IMVAMUNE® (1x10\^8 TCID50/0.5 mL per dose) lyophilized formulation by the subcutaneous route on Day 0 and 28. | 165 |
| Liquid, Subcutaneous Participants receive a 2 dose regimen of IMVAMUNE® (1x10\^8 TCID50/0.5 mL per dose) liquid formulation by the subcutaneous route on Day 0 and 28. | 167 |
| Liquid, Intradermal Participants receive a 2 dose regimen of IMVAMUNE® (2x10\^7 TCID50/0.1mL per dose) liquid formulation by the intradermal route on Day 0 and 28. | 191 |
| Total | 523 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 6 | 7 | 9 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 2 |
Baseline characteristics
| Characteristic | Lyophilized, Subcutaneous | Liquid, Subcutaneous | Liquid, Intradermal | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 165 Participants | 167 Participants | 191 Participants | 523 Participants |
| Age, Continuous | 27.0 years STANDARD_DEVIATION 4.4 | 26.8 years STANDARD_DEVIATION 4.5 | 27.7 years STANDARD_DEVIATION 4.9 | 27.2 years STANDARD_DEVIATION 4.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 17 Participants | 12 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 159 Participants | 150 Participants | 179 Participants | 488 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 6 Participants | 5 Participants | 21 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 13 Participants | 19 Participants | 50 Participants |
| Race (NIH/OMB) More than one race | 8 Participants | 3 Participants | 8 Participants | 19 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 129 Participants | 144 Participants | 156 Participants | 429 Participants |
| Region of Enrollment United States | 165 participants | 167 participants | 191 participants | 523 participants |
| Sex: Female, Male Female | 81 Participants | 80 Participants | 102 Participants | 263 Participants |
| Sex: Female, Male Male | 84 Participants | 87 Participants | 89 Participants | 260 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 165 | 0 / 167 | 0 / 191 |
| other Total, other adverse events | 164 / 165 | 161 / 167 | 191 / 191 |
| serious Total, serious adverse events | 1 / 165 | 2 / 167 | 1 / 191 |
Outcome results
Primary
Geometric Mean Titer (GMT) Based on Vaccinia-specific Individual Peak Plaque Reduction Neutralization Titers (PRNT) Following 2 Doses of IMVAMUNE® Lyophilized Versus Following 2 Doses of IMVAMUNE® Liquid Administered Subcutaneously, ITT Population
Blood was collected from participants for testing in the PRNT assay with vaccinia-Western Reserve (replicating vaccinia) as the assay antigen. The geometric mean titers were calculated for each participant's individual peak titer after second vaccination. Titer values below limit of detection were replaced by 7.5 (half the lower limit of detection) for analysis.
Time frame: Days 14, 28 and 180 after 2nd vaccination
Population: The ITT analysis population for the immunogenicity summaries include all participants with results for the visit. Participants were analyzed as randomized. Not receiving the second vaccination or second vaccination being out of window was not considered.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Lyophilized, Subcutaneous | Geometric Mean Titer (GMT) Based on Vaccinia-specific Individual Peak Plaque Reduction Neutralization Titers (PRNT) Following 2 Doses of IMVAMUNE® Lyophilized Versus Following 2 Doses of IMVAMUNE® Liquid Administered Subcutaneously, ITT Population | 77.9 titer |
| Liquid, Subcutaneous | Geometric Mean Titer (GMT) Based on Vaccinia-specific Individual Peak Plaque Reduction Neutralization Titers (PRNT) Following 2 Doses of IMVAMUNE® Lyophilized Versus Following 2 Doses of IMVAMUNE® Liquid Administered Subcutaneously, ITT Population | 46.7 titer |
Comparison: The sample size calculations targeted at least 80% power to test non-inferiority for the primary and secondary immunogenicity end points for two investigational arms in reference to a control arm. Assuming a standard deviation of 2.8 for log2 peak PRNT or ELISA titer in each group, a non-inferiority margin of 2.0-fold, a type I error rate of 1.25% (Bonferroni adjusted for 2 comparisons), and drop-out rate of 10%, 165 participants in each group were to be enrolled to achieve 148 evaluable97.5% CI: [-1.23, -0.25]
Primary
GMT Based on Vaccinia-specific Individual Peak PRNT Following 2 Doses of IMVAMUNE® Lyophilized Versus Following 2 Doses of IMVAMUNE® Liquid Administered Subcutaneously, Per Protocol Population
Blood was collected from participants for testing in the PRNT assay with vaccinia-Western Reserve (replicating vaccinia) as the assay antigen. The geometric mean titers were calculated for each participant's individual peak titer after second vaccination. Titer values below limit of detection were replaced by 7.5 (half the lower limit of detection) for analysis.
Time frame: Days 14, 28 and 180 after 2nd vaccination
Population: The per protocol (PP) analysis population includes subjects who received two doses of vaccine in window and contributed both pre- and post-vaccination blood samples and had no major protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Lyophilized, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak PRNT Following 2 Doses of IMVAMUNE® Lyophilized Versus Following 2 Doses of IMVAMUNE® Liquid Administered Subcutaneously, Per Protocol Population | 87.8 titer |
| Liquid, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak PRNT Following 2 Doses of IMVAMUNE® Lyophilized Versus Following 2 Doses of IMVAMUNE® Liquid Administered Subcutaneously, Per Protocol Population | 49.5 titer |
Comparison: The sample size calculations targeted at least 80% power to test non-inferiority for the primary and secondary immunogenicity end points for two investigational arms in reference to a control arm. Assuming a standard deviation of 2.8 for log2 peak PRNT or ELISA titer in each group, a non-inferiority margin of 2.0-fold, a type I error rate of 1.25% (Bonferroni adjusted for 2 comparisons), and drop-out rate of 10%, 165 participants in each group were to be enrolled to achieve 148 evaluable97.5% CI: [-1.32, -0.33]
Primary
GMT Based on Vaccinia-specific Individual Peak PRNT, Following 2 (Lower) Doses Liquid IMVAMUNE® Administered Intradermally Versus 2 (Higher) Doses of Liquid IMVAMUNE® Administered Subcutaneously, ITT Population
Blood was collected from participants for testing in the PRNT assay with vaccinia-Western Reserve (replicating vaccinia) as the assay antigen. The geometric mean titers were calculated for each participant's individual peak titer after second vaccination. Titer values below limit of detection were replaced by 7.5 (half the lower limit of detection) for analysis.
Time frame: Days 14, 28 and 180 after 2nd vaccination
Population: The ITT analysis population for the immunogenicity summaries include all participants with results for the visit. Participants were analyzed as randomized. Not receiving the second vaccination or second vaccination being out of window was not considered.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Lyophilized, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak PRNT, Following 2 (Lower) Doses Liquid IMVAMUNE® Administered Intradermally Versus 2 (Higher) Doses of Liquid IMVAMUNE® Administered Subcutaneously, ITT Population | 45.2 titer |
| Liquid, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak PRNT, Following 2 (Lower) Doses Liquid IMVAMUNE® Administered Intradermally Versus 2 (Higher) Doses of Liquid IMVAMUNE® Administered Subcutaneously, ITT Population | 46.7 titer |
Comparison: The sample size calculations targeted at least 80% power to test non-inferiority for the primary and secondary immunogenicity end points for two investigational arms in reference to a control arm. Assuming a standard deviation of 2.8 for log2 peak PRNT or ELISA titer in each group, a non-inferiority margin of 2.0-fold, a type I error rate of 1.25% (Bonferroni adjusted for 2 comparisons), and drop-out rate of 10%, 165 participants in each group were to be enrolled to achieve 148 evaluable.97.5% CI: [-0.43, 0.52]
Primary
GMT Based on Vaccinia-specific Individual Peak PRNT, Following 2 (Lower) Doses Liquid IMVAMUNE® Administered Intradermally Versus 2 (Higher) Doses of Liquid IMVAMUNE® Administered Subcutaneously, Per Protocol Population
Blood was collected from participants for testing in the PRNT assay with vaccinia-Western Reserve (replicating vaccinia) as the assay antigen. The geometric mean titers were calculated for each timepoint as well as for the peak titer after second vaccination. Titer values below limit of detection were replaced by 7.5 (half the lower limit of detection) for analysis.
Time frame: Days 14, 28 and 180 after 2nd vaccination
Population: The per protocol (PP) analysis population includes subjects who received two doses of vaccine in window and contributed both pre- and post-vaccination blood samples and had no major protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Lyophilized, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak PRNT, Following 2 (Lower) Doses Liquid IMVAMUNE® Administered Intradermally Versus 2 (Higher) Doses of Liquid IMVAMUNE® Administered Subcutaneously, Per Protocol Population | 59.6 titer |
| Liquid, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak PRNT, Following 2 (Lower) Doses Liquid IMVAMUNE® Administered Intradermally Versus 2 (Higher) Doses of Liquid IMVAMUNE® Administered Subcutaneously, Per Protocol Population | 49.5 titer |
Comparison: The sample size calculations targeted at least 80% power to test non-inferiority for the primary and secondary immunogenicity end points for two investigational arms in reference to a control arm. Assuming a standard deviation of 2.8 for log2 peak PRNT or ELISA titer in each group, a non-inferiority margin of 2.0-fold, a type I error rate of 1.25% (Bonferroni adjusted for 2 comparisons), and drop-out rate of 10%, 165 participants in each group were to be enrolled to achieve 148 evaluable.97.5% CI: [-0.77, 0.23]
Primary
Number of Participants Reporting Serious Adverse Events Associated With IMVAMUNE® Vaccination
An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Those SAEs considered associated are those with a known temporal relationship, or the event is known to occur in association with study product or with a product in a similar class of study products AND no alternate etiology is identified.
Time frame: Day 0 through 180 days after second vaccination
Population: The safety population includes all participants receiving at least one vaccination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lyophilized, Subcutaneous | Number of Participants Reporting Serious Adverse Events Associated With IMVAMUNE® Vaccination | 0 participants |
| Liquid, Subcutaneous | Number of Participants Reporting Serious Adverse Events Associated With IMVAMUNE® Vaccination | 0 participants |
| Liquid, Intradermal | Number of Participants Reporting Serious Adverse Events Associated With IMVAMUNE® Vaccination | 0 participants |
Secondary
GMT Based on Vaccinia-specific Individual Peak ELISA Titers, Following 2 Doses (Lower) Liquid Formulation IMVAMUNE® Administered Intradermally Versus That Obtained Following 2 Doses IMVAMUNE® Liquid Formulation Administered Subcutaneously, ITT Population
Blood was collected from participants for testing in the ELISA assay with IMVAMUNE (non-replicating vaccinia in humans) as the assay antigen. The geometric mean titers were calculated for each participant's individual peak titer after second vaccination. Titer values below limit of detection were replaced by 25 (half the lower limit of detection) for analysis.
Time frame: Days 14, 28 and 180 after 2nd vaccination
Population: The ITT analysis population for the immunogenicity summaries include all participants with results for the visit. Participants were analyzed as randomized. Not receiving the second vaccination or second vaccination being out of window was not considered.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Lyophilized, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak ELISA Titers, Following 2 Doses (Lower) Liquid Formulation IMVAMUNE® Administered Intradermally Versus That Obtained Following 2 Doses IMVAMUNE® Liquid Formulation Administered Subcutaneously, ITT Population | 554.0 titer |
| Liquid, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak ELISA Titers, Following 2 Doses (Lower) Liquid Formulation IMVAMUNE® Administered Intradermally Versus That Obtained Following 2 Doses IMVAMUNE® Liquid Formulation Administered Subcutaneously, ITT Population | 700.5 titer |
Comparison: The sample size calculations targeted at least 80% power to test non-inferiority for the primary and secondary immunogenicity end points for two investigational arms in reference to a control arm. Assuming a standard deviation of 2.8 for log2 peak PRNT or ELISA titer in each group, a non-inferiority margin of 2.0-fold, a type I error rate of 1.25% (Bonferroni adjusted for 2 comparisons), and drop-out rate of 10%, 165 participants in each group were to be enrolled to achieve 148 evaluable.97.5% CI: [-0.3, 0.71]
Secondary
GMT Based on Vaccinia-specific Individual Peak ELISA Titers, Following 2 Doses (Lower) Liquid Formulation IMVAMUNE® Administered Intradermally Versus That Obtained Following 2 Doses IMVAMUNE® Liquid Formulation Subcutaneously, Per Protocol Population
Blood was collected from participants for testing in the ELISA assay with IMVAMUNE (non-replicating vaccinia in humans) as the assay antigen. The geometric mean titers were calculated for each participant's individual peak titer after second vaccination. Titer values below limit of detection were replaced by 25 (half the lower limit of detection) for analysis.
Time frame: Days 14, 28 and 180 after second vaccination
Population: The per protocol (PP) analysis population includes subjects who received two doses of vaccine in window and contributed both pre- and post-vaccination blood samples and had no major protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Lyophilized, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak ELISA Titers, Following 2 Doses (Lower) Liquid Formulation IMVAMUNE® Administered Intradermally Versus That Obtained Following 2 Doses IMVAMUNE® Liquid Formulation Subcutaneously, Per Protocol Population | 757.9 titer |
| Liquid, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak ELISA Titers, Following 2 Doses (Lower) Liquid Formulation IMVAMUNE® Administered Intradermally Versus That Obtained Following 2 Doses IMVAMUNE® Liquid Formulation Subcutaneously, Per Protocol Population | 769.3 titer |
Comparison: The sample size calculations targeted at least 80% power to test non-inferiority for the primary and secondary immunogenicity end points for two investigational arms in reference to a control arm. Assuming a standard deviation of 2.8 for log2 peak PRNT or ELISA titer in each group, a non-inferiority margin of 2.0-fold, a type I error rate of 1.25% (Bonferroni adjusted for 2 comparisons), and drop-out rate of 10%, 165 participants in each group were to be enrolled to achieve 148 evaluable.97.5% CI: [-0.31, 0.35]
Secondary
GMT Based on Vaccinia-specific Individual Peak ELISA Titers Following 2 Doses of IMVAMUNE® Lyophilized Formulation Versus That Obtained Following 2 Doses of IMVAMUNE® Liquid Formulation Subcutaneously, ITT Population.
Blood was collected from participants for testing in the ELISA assay with IMVAMUNE (non-replicating vaccinia in humans) as the assay antigen. The geometric mean titers were calculated using the individual peak titer after second vaccination. Titer values below limit of detection were replaced by 25 (half the lower limit of detection) for analysis.
Time frame: Days 14, 28 and 180 after 2nd vaccination.
Population: The ITT analysis population for the immunogenicity summaries include all participants with results for the visit. Participants were analyzed as randomized. Not receiving the second vaccination or second vaccination being out of window was not considered.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Lyophilized, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak ELISA Titers Following 2 Doses of IMVAMUNE® Lyophilized Formulation Versus That Obtained Following 2 Doses of IMVAMUNE® Liquid Formulation Subcutaneously, ITT Population. | 893.5 titer |
| Liquid, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak ELISA Titers Following 2 Doses of IMVAMUNE® Lyophilized Formulation Versus That Obtained Following 2 Doses of IMVAMUNE® Liquid Formulation Subcutaneously, ITT Population. | 700.5 titer |
Comparison: The sample size calculations targeted at least 80% power to test non-inferiority for the primary and secondary immunogenicity end points for two investigational arms in reference to a control arm. Assuming a standard deviation of 2.8 for log2 peak PRNT or ELISA titer in each group, a non-inferiority margin of 2.0-fold, a type I error rate of 1.25% (Bonferroni adjusted for 2 comparisons), and drop-out rate of 10%, 165 participants in each group were to be enrolled to achieve 148 evaluable.97.5% CI: [-0.74, 0.04]
Secondary
GMT Based on Vaccinia-specific Individual Peak ELISA Titers Following 2 Doses of IMVAMUNE® Lyophilized Formulation Versus That Obtained Following 2 Doses of IMVAMUNE® Liquid Formulation Subcutaneously, Per Protocol Population.
Blood was collected from participants for testing in the ELISA assay with IMVAMUNE (non-replicating vaccinia in humans) as the assay antigen. The geometric mean titers were calculated using the individual peak titer after second vaccination. Titer values below limit of detection were replaced by 25 (half the lower limit of detection) for analysis.
Time frame: Days 14, 28 and 180 after 2nd vaccination.
Population: The per protocol (PP) analysis population includes subjects who received two doses of vaccine in window and contributed both pre- and post-vaccination blood samples and had no major protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Lyophilized, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak ELISA Titers Following 2 Doses of IMVAMUNE® Lyophilized Formulation Versus That Obtained Following 2 Doses of IMVAMUNE® Liquid Formulation Subcutaneously, Per Protocol Population. | 1062.4 titer |
| Liquid, Subcutaneous | GMT Based on Vaccinia-specific Individual Peak ELISA Titers Following 2 Doses of IMVAMUNE® Lyophilized Formulation Versus That Obtained Following 2 Doses of IMVAMUNE® Liquid Formulation Subcutaneously, Per Protocol Population. | 769.3 titer |
Comparison: The sample size calculations targeted at least 80% power to test non-inferiority for the primary and secondary immunogenicity end points for two investigational arms in reference to a control arm. Assuming a standard deviation of 2.8 for log2 peak PRNT or ELISA titer in each group, a non-inferiority margin of 2.0-fold, a type I error rate of 1.25% (Bonferroni adjusted for 2 comparisons), and drop-out rate of 10%, 165 participants in each group were to be enrolled to achieve 148 evaluable.97.5% CI: [-0.81, -0.12]
Secondary
Number of Participants Assessed With Grade 3 and 4 Laboratory Toxicities Associated With IMVAMUNE®.
Safety laboratory parameters included hemoglobin, white blood cells (WBC), platelets, ALT, and serum creatinine. These parameters were evaluated at Day 0 and 14 days after vaccination. Thresholds for Grade 3 or 4 were hemoglobin less than 8.0 g/dL, WBC less than 2000 cells/mm\^3, platelets less than 50,000 cells/mm\^3, ALT 5.0 times the upper limit of normal (ULN) or greater, and serum creatinine of 1.9 times ULN or greater. Associated with IMVAMUNE was defined as a known temporal relationship, or the event is known to occur in association with study product or with a product in a similar class of study products AND no alternate etiology is identified.
Time frame: Days 0, 14 and 42
Population: The safety population includes all participants receiving at least one vaccination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lyophilized, Subcutaneous | Number of Participants Assessed With Grade 3 and 4 Laboratory Toxicities Associated With IMVAMUNE®. | 0 participants |
| Liquid, Subcutaneous | Number of Participants Assessed With Grade 3 and 4 Laboratory Toxicities Associated With IMVAMUNE®. | 0 participants |
| Liquid, Intradermal | Number of Participants Assessed With Grade 3 and 4 Laboratory Toxicities Associated With IMVAMUNE®. | 0 participants |