Smallpox
Conditions
Brief summary
A randomized, double-blind, multicenter Phase II trial to compare the immunogenicity and safety of a liquid-frozen and a freeze-dried formulation of IMVAMUNE (MVA-BN®) smallpox vaccine in vaccinia-naïve healthy subjects
Interventions
BIOLOGICALLF formulation of IMVAMUNE®
BIOLOGICALFD formulation of IMVAMUNE®
Sponsors
Bavarian Nordic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male and female subjects, 18-55 years of age 2. The subject has read, signed and dated informed consent form, having been advised of the risks and benefits of the trial in a language understood by the subject and prior to performance of any trial specific procedures and has signed the Health Insurance Portability and Accountability Act (HIPAA) authorization form 3. Body Mass Index (BMI) ≥ 18.5 and \< 35 4. Women of childbearing potential (WOCBP) must have used an acceptable method of contraception for 30 days prior to the first vaccination, must agree to use an acceptable method of contraception during the trial, and must avoid becoming pregnant for at least 28 days after the last vaccination. A woman is considered of childbearing potential unless post-menopausal or with a history of hysterectomy. (Acceptable contraception methods are restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products) 5. WOCBP must have a negative serum pregnancy test at screening (SCR) and a negative urine pregnancy test within 24 hours prior to each vaccination 6. White blood cells ≥ 2500/mm3 and \< ULN 7. Absolute neutrophil count (ANC) within normal limits 8. Hemoglobin within normal limits 9. Platelets within normal limits 10. Adequate renal function defined as a calculated Creatinine Clearance (CrCl) \> 60 ml/min as estimated by the Cockcroft-Gault equation: * For men: (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dl x 72) = CrCl (ml/min) * For women: multiply the result by 0.85 = CrCl (ml/min) 11. Adequate hepatic function defined as: * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) in the absence of other evidence of significant liver disease * Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase \< 1.5 x ULN 12. Troponin I \< 2 x ULN 13. Electrocardiogram (ECG) without clinically significant findings, e.g. any kind of atrioventricular or intraventricular conditions or blocks such as complete left or right bundle branch block, AV node block, QTc or PR prolongation, premature atrial contractions or other atrial arrhythmia, sustained ventricular arrhythmia, two premature ventricular contractions (PVC) in a row, ST elevation consistent with ischemia
Exclusion criteria
1. Typical vaccinia scar 2. Known or suspected history of smallpox vaccination 3. History of vaccination with any poxvirus-based vaccine 4. US Military service before 1991 or after January 2003 5. Pregnant or breast-feeding women 6. Uncontrolled serious infection, i.e. not responding to antimicrobial therapy 7. History of any serious medical condition, which in the opinion of the investigator would compromise the safety of the subject or would limit the subject's ability to complete the trial in the opinion of the investigator 8. History of or active autoimmune disease, persons with vitiligo or thyroid disease taking thyroid hormone replacement are not excluded 9. Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease, diabetes mellitus, moderate to severe kidney impairment 10. History of malignancy, other than squamous cell or basal cell skin cancer, unless there has been surgical excision that is considered to have achieved cure. Subjects with history of skin cancer must not be vaccinated at the previous tumor site 11. History or clinical manifestation of clinically significant and severe hematological, pulmonary, central nervous, cardiovascular or gastrointestinal disorders 12. Clinically significant mental disorder not adequately controlled by medical treatment 13. History of coronary heart disease, myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, uncontrolled high blood pressure, or any other heart condition under the care of a doctor 14. History of an immediate family member (father, mother, brother, or sister) who has had onset of ischemic heart disease before the age of 50 years 15. Twenty 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: This criterion applies only to subjects 20 years of age and older 16. Active or history of chronic alcohol abuse and/or intravenous and/or nasal drug abuse (within the past 6 months) 17. Known allergy to IMVAMUNE® vaccine and its constituents, e.g. tris(hydroxymethyl)-amino methane, including known allergy to egg or aminoglycoside (gentamycin) 18. History of anaphylaxis or severe allergic reaction to any vaccine 19. Acute disease (illness with or without a fever) at the time of enrollment 20. Body Temperature ≥ 100.4°F (38.0°C) at the time of enrollment 21. Having received any vaccinations or planned vaccinations with a live vaccine within 30 days prior or after trial vaccination 22. Having received any vaccinations or planned vaccinations with a killed vaccine within 14 days prior or after trial vaccination 23. Chronic systemic administration (defined as more than 14 days) of \> 5 mg prednisone (or equivalent)/day or any other immune-modifying drugs during a period starting from three months prior to administration of the vaccine and ending at last physical trial visit (Visit 5) 24. Post organ transplant subjects whether or not receiving chronic immunosuppressive therapy 25. Administration or planned administration of immunoglobulins and/or any blood products during a period starting from three months prior to administration of the vaccine and ending at last physical trial visit (Visit 5) 26. Use of any investigational or non-registered drug or vaccine other than the trial vaccine within 30 days preceding the first dose of the trial vaccine or planned administration of such a drug during the trial period (with the day of the FU call being considered the last day of the trial period). 27. Trial personnel
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ELISA GMT | Week 6 | Geometric Mean Titers (GMT) based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Titers below the detection limit are included with a value of '1' |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events | up to 32 weeks | Occurrence, relationship to the trial vaccine and intensity of any Serious Adverse Event (SAE). |
| Number of Participants With Adverse Events of Special Interest (AESI) | up to 32 weeks | Occurrence, relationship to the trial vaccine and intensity of any Adverse Event of Special Interest (AESI). AESIs were defined as any cardiac symptoms and ECG changes determined to be clinically significant or cardiac enzyme troponin I elevated above 2 x the Upper Limit of Normal |
| Number of Participants With Related Grade >=3 Adverse Events | within 29 days after vaccination | Occurrence of any Grade \>=3 Adverse Events related to the trial vaccine. |
| Number of Participants With Unsolicited Adverse Events | within 29 days after vaccination | Occurrence, relationship to the trial vaccine and intensity of unsolicited treatment-emergent AEs (TEAEs). |
| Number of Participants With Solicited Local Averse Events | 8 days after any vaccination | Occurrence and intensity of solicited local AEs (redness, swelling, induration, pruritus and pain) during the 8-day period (day of vaccination and the following 7 days) after any vaccination. Events were graded by intensity (1 = mild, 2 = moderate, 3 = severe). |
| Number of Participants With Solicited General Adverse Events | within 8 days after any vaccination | Occurrence, intensity and relationship to the trial vaccines of solicited general AEs (pyrexia, headache, myalgia, nausea, fatigue and chills) during the 8-day period (day of vaccination and the following 7 days) after any vaccination. Events were graded by intensity (1 = mild, 2 = moderate, 3 = severe). |
| ELISA GMTs | within 8 weeks | Geometric Mean Titers (GMT) at all immunogenicity sampling time points based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). For the calculation of GMTs all measurements are included as they provide meaningful information even if below the detection limit (DL). Disregarding these measurements would highly bias the reported GMTs. We imputed values \<DL as a value of '1' and the GMT and corresponding 95% confidence intervals were calculated. |
| Correlation ELISA vs PRNT Titers | within 8 weeks | Pearson Correlation Coefficient between the ELISA titers and the PRNT titers at weeks 4, 6 and 8 based on the log10 transformed titer values |
| PRNT GMTs | within 8 weeks | Geometric Mean Titers (GMT) at all immunogenicity sampling time points based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). For the calculation of GMTs all measurements are included as they provide meaningful information even if below the detection limit (DL). Disregarding these measurements would highly bias the reported GMTs. We imputed values \<DL as a value of '1' and the GMT and corresponding 95% confidence intervals were calculated. |
| Percentage of Participants With Seroconversion by ELISA | Week 6 | Seroconversion rate based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. |
| Percentage of Participants With Seroconversion by PRNT | Week 6 | Seroconversion rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (2) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. |
| ELISPOT Magnitudes of Response | within 8 weeks | Magnitudes of response of IFNγ producing T-cells measured by vaccinica-specific ELISPOT. Spot Forming Units below the detection limit are included as a value of '1'. |
| Percentage of Participants With Response by ELISPOT | within 8 weeks | Response rates regarding IFNγ producing T-cells measured by vaccinia-specific ELISPOT. A response to the vaccine was defined as either the appearance of a positive signal for participants without a positive signal at Baseline or an increase by a factor of at least 1.7 of the SFU/1 x 10E6 PBMC compared to the Baseline SFU/1 x 10E6 PBMC for participants with a positive signal at Baseline. |
| Percentage of Responders by ELISPOT | within 8 weeks | Responder rate measured by vaccinia specific ELISPOT. A participant was defined as a responder to the vaccine determined by ELISPOT if the participant had at least 1 post-baseline visit determined to be a response. A response to the vaccine was defined as either the appearance of a positive signal for participants without a positive signal at Baseline or an increase by a factor of at least 1.7 of the SFU/1 x 10E6 PBMC compared to the Baseline SFU/1 x 10E6 PBMC for participants with a positive signal at Baseline. |
| PRNT GMT | Week 6 | Geometric Mean Titers (GMT) based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Titers below the detection limit are included with a value of '1' |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LF Formulation Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart
LF formulation of MVA-BN® | 327 |
| FD Formulation Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart
FD formulation of MVA-BN® | 324 |
| Total | 651 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 13 | 6 |
| Overall Study | Other | 2 | 3 |
| Overall Study | Reason Precludes Participation | 1 | 0 |
| Overall Study | Request to Discontinue Prematurely | 1 | 1 |
| Overall Study | Subject unwilling/unable to comply | 5 | 0 |
Baseline characteristics
| Characteristic | LF Formulation | Total | FD Formulation |
|---|---|---|---|
| Age, Continuous | 27.8 years STANDARD_DEVIATION 6.36 | 27.7 years STANDARD_DEVIATION 6.28 | 27.6 years STANDARD_DEVIATION 6.21 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 95 Participants | 190 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 232 Participants | 461 Participants | 229 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 78 Participants | 145 Participants | 67 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 10 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 239 Participants | 486 Participants | 247 Participants |
| Region of Enrollment United States | 327 participants | 651 participants | 324 participants |
| Sex: Female, Male Female | 178 Participants | 348 Participants | 170 Participants |
| Sex: Female, Male Male | 149 Participants | 303 Participants | 154 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 327 | 0 / 324 |
| other Total, other adverse events | 115 / 327 | 114 / 324 |
| serious Total, serious adverse events | 5 / 327 | 2 / 324 |
Outcome results
Primary
ELISA GMT
Geometric Mean Titers (GMT) based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Titers below the detection limit are included with a value of '1'
Time frame: Week 6
Population: Per Protocol Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| LF Formulation | ELISA GMT | 875.1 Titer |
| FD Formulation | ELISA GMT | 1099.6 Titer |
95% CI: [0.707, 0.896]
Secondary
Correlation ELISA vs PRNT Titers
Pearson Correlation Coefficient between the ELISA titers and the PRNT titers at weeks 4, 6 and 8 based on the log10 transformed titer values
Time frame: within 8 weeks
Population: Per Protocol Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LF Formulation | Correlation ELISA vs PRNT Titers | Week 4 | 0.597 Pearson Correlation Coefficient |
| LF Formulation | Correlation ELISA vs PRNT Titers | Week 6 | 0.646 Pearson Correlation Coefficient |
| LF Formulation | Correlation ELISA vs PRNT Titers | Week 8 | 0.567 Pearson Correlation Coefficient |
| FD Formulation | Correlation ELISA vs PRNT Titers | Week 6 | 0.553 Pearson Correlation Coefficient |
| FD Formulation | Correlation ELISA vs PRNT Titers | Week 4 | 0.492 Pearson Correlation Coefficient |
| FD Formulation | Correlation ELISA vs PRNT Titers | Week 8 | 0.565 Pearson Correlation Coefficient |
Secondary
ELISA GMTs
Geometric Mean Titers (GMT) at all immunogenicity sampling time points based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). For the calculation of GMTs all measurements are included as they provide meaningful information even if below the detection limit (DL). Disregarding these measurements would highly bias the reported GMTs. We imputed values \<DL as a value of '1' and the GMT and corresponding 95% confidence intervals were calculated.
Time frame: within 8 weeks
Population: Per Protocol Analysis Set. Number Analyzed refers to the number of participants with measurements at the respective sampling time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| LF Formulation | ELISA GMTs | Week 0 | 1.1 Titer |
| LF Formulation | ELISA GMTs | Week 2 | 56.0 Titer |
| LF Formulation | ELISA GMTs | Week 4 | 89.6 Titer |
| LF Formulation | ELISA GMTs | Week 6 | 875.1 Titer |
| LF Formulation | ELISA GMTs | Week 8 | 546.4 Titer |
| FD Formulation | ELISA GMTs | Week 6 | 1099.6 Titer |
| FD Formulation | ELISA GMTs | Week 0 | 1.1 Titer |
| FD Formulation | ELISA GMTs | Week 8 | 689.0 Titer |
| FD Formulation | ELISA GMTs | Week 4 | 131.3 Titer |
| FD Formulation | ELISA GMTs | Week 2 | 90.4 Titer |
Secondary
ELISPOT Magnitudes of Response
Magnitudes of response of IFNγ producing T-cells measured by vaccinica-specific ELISPOT. Spot Forming Units below the detection limit are included as a value of '1'.
Time frame: within 8 weeks
Population: ELISPOT Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LF Formulation | ELISPOT Magnitudes of Response | Week 8 | 145.5 Spot Forming Units |
| LF Formulation | ELISPOT Magnitudes of Response | Week 0 | 1.0 Spot Forming Units |
| LF Formulation | ELISPOT Magnitudes of Response | Week 2 | 393.0 Spot Forming Units |
| LF Formulation | ELISPOT Magnitudes of Response | Week 4 | 88.0 Spot Forming Units |
| LF Formulation | ELISPOT Magnitudes of Response | Week 6 | 235.0 Spot Forming Units |
| FD Formulation | ELISPOT Magnitudes of Response | Week 6 | 315.0 Spot Forming Units |
| FD Formulation | ELISPOT Magnitudes of Response | Week 4 | 133.0 Spot Forming Units |
| FD Formulation | ELISPOT Magnitudes of Response | Week 0 | 1.0 Spot Forming Units |
| FD Formulation | ELISPOT Magnitudes of Response | Week 8 | 240.0 Spot Forming Units |
| FD Formulation | ELISPOT Magnitudes of Response | Week 2 | 581.5 Spot Forming Units |
Secondary
Number of Participants With Adverse Events of Special Interest (AESI)
Occurrence, relationship to the trial vaccine and intensity of any Adverse Event of Special Interest (AESI). AESIs were defined as any cardiac symptoms and ECG changes determined to be clinically significant or cardiac enzyme troponin I elevated above 2 x the Upper Limit of Normal
Time frame: up to 32 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LF Formulation | Number of Participants With Adverse Events of Special Interest (AESI) | AESI | 1 Participants |
| LF Formulation | Number of Participants With Adverse Events of Special Interest (AESI) | Drug-related AESI | 0 Participants |
| LF Formulation | Number of Participants With Adverse Events of Special Interest (AESI) | AESI Grade >=3 | 0 Participants |
| FD Formulation | Number of Participants With Adverse Events of Special Interest (AESI) | AESI | 4 Participants |
| FD Formulation | Number of Participants With Adverse Events of Special Interest (AESI) | Drug-related AESI | 0 Participants |
| FD Formulation | Number of Participants With Adverse Events of Special Interest (AESI) | AESI Grade >=3 | 0 Participants |
Secondary
Number of Participants With Related Grade >=3 Adverse Events
Occurrence of any Grade \>=3 Adverse Events related to the trial vaccine.
Time frame: within 29 days after vaccination
Population: Full Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LF Formulation | Number of Participants With Related Grade >=3 Adverse Events | 0 Participants |
| FD Formulation | Number of Participants With Related Grade >=3 Adverse Events | 1 Participants |
Secondary
Number of Participants With Serious Adverse Events
Occurrence, relationship to the trial vaccine and intensity of any Serious Adverse Event (SAE).
Time frame: up to 32 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LF Formulation | Number of Participants With Serious Adverse Events | SAE | 5 Participants |
| LF Formulation | Number of Participants With Serious Adverse Events | SAE related to vaccine | 0 Participants |
| LF Formulation | Number of Participants With Serious Adverse Events | SAE Grade >=3 | 3 Participants |
| FD Formulation | Number of Participants With Serious Adverse Events | SAE | 2 Participants |
| FD Formulation | Number of Participants With Serious Adverse Events | SAE related to vaccine | 0 Participants |
| FD Formulation | Number of Participants With Serious Adverse Events | SAE Grade >=3 | 1 Participants |
Secondary
Number of Participants With Solicited General Adverse Events
Occurrence, intensity and relationship to the trial vaccines of solicited general AEs (pyrexia, headache, myalgia, nausea, fatigue and chills) during the 8-day period (day of vaccination and the following 7 days) after any vaccination. Events were graded by intensity (1 = mild, 2 = moderate, 3 = severe).
Time frame: within 8 days after any vaccination
Population: Subjects of the Full Analysis Set with at least one completed diary card
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LF Formulation | Number of Participants With Solicited General Adverse Events | Myalgia : All | 68 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Fatigue : Grade =3 | 15 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Myalgia : Grade >=2 | 24 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Body Temperature increased : Related | 22 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Myalgia : Grade =3 | 1 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Myalgia : Related | 59 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Myalgia : Related Grade =3 | 1 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Body Temperature increased : Related Grade =3 | 3 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Chills : All | 38 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Fatigue : Related | 106 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Chills : Grade >=2 | 14 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Headache : All | 125 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Chills : Grade =3 | 2 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Body Temperature increased : All | 23 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Chills : Related | 34 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Headache : Grade >=2 | 37 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Chills : Related Grade =3 | 2 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Fatigue : Grade >=2 | 39 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Nausea : All | 57 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Headache : Grade =3 | 8 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Nausea : Grade >=2 | 19 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Body Temperature increased : Grade >=2 | 7 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Nausea : Related | 53 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Headache : Related | 110 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Nausea : Related Grade =3 | 4 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Nausea : Grade =3 | 4 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Fatigue : All | 113 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Headache : Related Grade =3 | 6 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Fatigue : Related Grade =3 | 14 participants |
| LF Formulation | Number of Participants With Solicited General Adverse Events | Body Temperature increased : Grade =3 | 3 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Fatigue : Related Grade =3 | 9 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Nausea : Grade >=2 | 18 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Fatigue : All | 102 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Fatigue : Grade >=2 | 39 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Fatigue : Grade =3 | 9 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Body Temperature increased : All | 33 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Body Temperature increased : Grade >=2 | 8 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Body Temperature increased : Grade =3 | 2 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Body Temperature increased : Related | 30 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Body Temperature increased : Related Grade =3 | 2 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Headache : All | 112 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Headache : Grade >=2 | 27 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Headache : Grade =3 | 7 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Headache : Related | 94 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Headache : Related Grade =3 | 6 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Myalgia : All | 59 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Myalgia : Grade >=2 | 18 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Myalgia : Related | 47 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Myalgia : Related Grade =3 | 3 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Chills : All | 35 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Chills : Grade >=2 | 10 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Chills : Grade =3 | 5 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Chills : Related | 33 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Chills : Related Grade =3 | 4 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Nausea : All | 51 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Nausea : Grade =3 | 2 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Nausea : Related | 44 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Nausea : Related Grade =3 | 2 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Fatigue : Related | 95 participants |
| FD Formulation | Number of Participants With Solicited General Adverse Events | Myalgia : Grade =3 | 5 participants |
Secondary
Number of Participants With Solicited Local Averse Events
Occurrence and intensity of solicited local AEs (redness, swelling, induration, pruritus and pain) during the 8-day period (day of vaccination and the following 7 days) after any vaccination. Events were graded by intensity (1 = mild, 2 = moderate, 3 = severe).
Time frame: 8 days after any vaccination
Population: Subjects of the Full Analysis Set with at least one completed diary card
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site swelling : All | 210 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site induration : Grade >=2 | 73 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site erythema : All | 247 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site induration : Grade =3 | 5 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site swelling : Grade >=2 | 94 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site pruritus : All | 177 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site erythema : Grade =3 | 16 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site pruritus : Grade >=2 | 38 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site swelling : Grade =3 | 10 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site pruritus : Grade =3 | 7 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site pain : All | 274 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site erythema : Grade >=2 | 140 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site pain : Grade >=2 | 138 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site induration : All | 211 participants |
| LF Formulation | Number of Participants With Solicited Local Averse Events | Injection site pain : Grade =3 | 22 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site induration : All | 213 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site erythema : Grade =3 | 47 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site pain : Grade =3 | 35 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site erythema : All | 255 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site erythema : Grade >=2 | 181 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site swelling : All | 223 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site swelling : Grade >=2 | 125 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site swelling : Grade =3 | 23 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site pruritus : Grade =3 | 11 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site induration : Grade >=2 | 96 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site induration : Grade =3 | 6 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site pruritus : All | 189 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site pruritus : Grade >=2 | 47 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site pain : All | 290 participants |
| FD Formulation | Number of Participants With Solicited Local Averse Events | Injection site pain : Grade >=2 | 167 participants |
Secondary
Number of Participants With Unsolicited Adverse Events
Occurrence, relationship to the trial vaccine and intensity of unsolicited treatment-emergent AEs (TEAEs).
Time frame: within 29 days after vaccination
Population: Full Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LF Formulation | Number of Participants With Unsolicited Adverse Events | TEAE | 313 Participants |
| LF Formulation | Number of Participants With Unsolicited Adverse Events | Drug-Related TEAE | 207 Participants |
| LF Formulation | Number of Participants With Unsolicited Adverse Events | TEAE Grade >=3 | 6 Participants |
| LF Formulation | Number of Participants With Unsolicited Adverse Events | Drug-Related TEAE Grade >=3 | 0 Participants |
| FD Formulation | Number of Participants With Unsolicited Adverse Events | Drug-Related TEAE Grade >=3 | 1 Participants |
| FD Formulation | Number of Participants With Unsolicited Adverse Events | TEAE | 310 Participants |
| FD Formulation | Number of Participants With Unsolicited Adverse Events | TEAE Grade >=3 | 5 Participants |
| FD Formulation | Number of Participants With Unsolicited Adverse Events | Drug-Related TEAE | 207 Participants |
Secondary
Percentage of Participants With Response by ELISPOT
Response rates regarding IFNγ producing T-cells measured by vaccinia-specific ELISPOT. A response to the vaccine was defined as either the appearance of a positive signal for participants without a positive signal at Baseline or an increase by a factor of at least 1.7 of the SFU/1 x 10E6 PBMC compared to the Baseline SFU/1 x 10E6 PBMC for participants with a positive signal at Baseline.
Time frame: within 8 weeks
Population: ELISPOT Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LF Formulation | Percentage of Participants With Response by ELISPOT | Week 4 | 66.0 percentage of subjects |
| LF Formulation | Percentage of Participants With Response by ELISPOT | Week 2 | 95.0 percentage of subjects |
| LF Formulation | Percentage of Participants With Response by ELISPOT | Week 6 | 88.0 percentage of subjects |
| LF Formulation | Percentage of Participants With Response by ELISPOT | Week 8 | 84.0 percentage of subjects |
| FD Formulation | Percentage of Participants With Response by ELISPOT | Week 8 | 92.3 percentage of subjects |
| FD Formulation | Percentage of Participants With Response by ELISPOT | Week 2 | 97.9 percentage of subjects |
| FD Formulation | Percentage of Participants With Response by ELISPOT | Week 4 | 80.2 percentage of subjects |
| FD Formulation | Percentage of Participants With Response by ELISPOT | Week 6 | 94.4 percentage of subjects |
Secondary
Percentage of Participants With Seroconversion by ELISA
Seroconversion rate based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects.
Time frame: Week 6
Population: Per Protocol Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LF Formulation | Percentage of Participants With Seroconversion by ELISA | 100.0 percentage of subjects |
| FD Formulation | Percentage of Participants With Seroconversion by ELISA | 100.0 percentage of subjects |
Secondary
Percentage of Participants With Seroconversion by ELISA
Seroconversion rates at all post-baseline immunogenicity sampling time points based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available.
Time frame: within 8 weeks
Population: Per Protocol Analysis Set. Number Analyzed refers to the number of participants with measurements at the respective sampling time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LF Formulation | Percentage of Participants With Seroconversion by ELISA | Week 2 | 83.5 percentage of subjects |
| LF Formulation | Percentage of Participants With Seroconversion by ELISA | Week 4 | 91.9 percentage of subjects |
| LF Formulation | Percentage of Participants With Seroconversion by ELISA | Week 6 | 100.0 percentage of subjects |
| LF Formulation | Percentage of Participants With Seroconversion by ELISA | Week 8 | 100.0 percentage of subjects |
| FD Formulation | Percentage of Participants With Seroconversion by ELISA | Week 8 | 100.0 percentage of subjects |
| FD Formulation | Percentage of Participants With Seroconversion by ELISA | Week 2 | 91.5 percentage of subjects |
| FD Formulation | Percentage of Participants With Seroconversion by ELISA | Week 6 | 100.0 percentage of subjects |
| FD Formulation | Percentage of Participants With Seroconversion by ELISA | Week 4 | 97.0 percentage of subjects |
Secondary
Percentage of Participants With Seroconversion by PRNT
Seroconversion rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (2) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects.
Time frame: Week 6
Population: Per Protocol Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LF Formulation | Percentage of Participants With Seroconversion by PRNT | 99.0 percentage of subjects |
| FD Formulation | Percentage of Participants With Seroconversion by PRNT | 100.0 percentage of subjects |
Secondary
Percentage of Participants With Seroconversion by PRNT
Seroconversion rates at all post-baseline immunogenicity sampling time points based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (2) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available.
Time frame: within 8 weeks
Population: Per Protocol Analysis Set. Number Analyzed refers to the number of participants with measurements at the respective sampling time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LF Formulation | Percentage of Participants With Seroconversion by PRNT | Week 6 | 99.0 percentage of subjects |
| LF Formulation | Percentage of Participants With Seroconversion by PRNT | Week 4 | 84.8 percentage of subjects |
| LF Formulation | Percentage of Participants With Seroconversion by PRNT | Week 8 | 100.0 percentage of subjects |
| LF Formulation | Percentage of Participants With Seroconversion by PRNT | Week 2 | 80.1 percentage of subjects |
| FD Formulation | Percentage of Participants With Seroconversion by PRNT | Week 8 | 99.7 percentage of subjects |
| FD Formulation | Percentage of Participants With Seroconversion by PRNT | Week 4 | 91.5 percentage of subjects |
| FD Formulation | Percentage of Participants With Seroconversion by PRNT | Week 6 | 100.0 percentage of subjects |
| FD Formulation | Percentage of Participants With Seroconversion by PRNT | Week 2 | 87.3 percentage of subjects |
Secondary
Percentage of Responders by ELISPOT
Responder rate measured by vaccinia specific ELISPOT. A participant was defined as a responder to the vaccine determined by ELISPOT if the participant had at least 1 post-baseline visit determined to be a response. A response to the vaccine was defined as either the appearance of a positive signal for participants without a positive signal at Baseline or an increase by a factor of at least 1.7 of the SFU/1 x 10E6 PBMC compared to the Baseline SFU/1 x 10E6 PBMC for participants with a positive signal at Baseline.
Time frame: within 8 weeks
Population: ELISPOT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LF Formulation | Percentage of Responders by ELISPOT | 100 percentage of subjects |
| FD Formulation | Percentage of Responders by ELISPOT | 100 percentage of subjects |
Secondary
PRNT GMT
Geometric Mean Titers (GMT) based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Titers below the detection limit are included with a value of '1'
Time frame: Week 6
Population: Per Protocol Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| LF Formulation | PRNT GMT | 81.8 Titer |
| FD Formulation | PRNT GMT | 101.2 Titer |
Secondary
PRNT GMTs
Geometric Mean Titers (GMT) at all immunogenicity sampling time points based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). For the calculation of GMTs all measurements are included as they provide meaningful information even if below the detection limit (DL). Disregarding these measurements would highly bias the reported GMTs. We imputed values \<DL as a value of '1' and the GMT and corresponding 95% confidence intervals were calculated.
Time frame: within 8 weeks
Population: Per Protocol Analysis Set. Number Analyzed refers to the number of participants with measurements at the respective sampling time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| LF Formulation | PRNT GMTs | Week 6 | 81.8 Titer |
| LF Formulation | PRNT GMTs | Week 8 | 59.7 Titer |
| LF Formulation | PRNT GMTs | Week 0 | 1.1 Titer |
| LF Formulation | PRNT GMTs | Week 2 | 7.1 Titer |
| LF Formulation | PRNT GMTs | Week 4 | 9.3 Titer |
| FD Formulation | PRNT GMTs | Week 4 | 12.5 Titer |
| FD Formulation | PRNT GMTs | Week 2 | 10.4 Titer |
| FD Formulation | PRNT GMTs | Week 8 | 76.1 Titer |
| FD Formulation | PRNT GMTs | Week 6 | 101.2 Titer |
| FD Formulation | PRNT GMTs | Week 0 | 1.0 Titer |