A Trial to Evaluate Immunogenicity and Safety of Three Consecutive Production Lots of IMVAMUNE® (MVA-BN®) Smallpox Vaccine in Healthy, Vaccinia-naïve Subjects

Phase 3

Completed

Conditions: Smallpox

Interventions: Biological: IMVAMUNE®
Other: Placebo

Registration Number: NCT01144637

Lead Sponsor: Bavarian Nordic

Brief Summary: A randomized, double-blind, placebo-controlled Phase III trial to evaluate immunogenicity and safety of three consecutive production lots of IMVAMUNE® (MVA-BN®) smallpox vaccine in healthy, vaccinia-naïve subjects.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 4005

Inclusion Criteria

Male and female subjects, 18 to 40 years of age
The subject has read, signed and dated the 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
BMI ≥ 18.5 and < 35
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)
WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test within 24 hours prior to each vaccination
White blood cells ≥ 2,500/mm3 < ULN
Absolute neutrophil count (ANC) within normal limits
Hemoglobin within normal limits
Platelets within normal limits
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).
Adequate hepatic function defined as:
- a. Total bilirubin ≤ 1.5 x ULN in the absence of other evidence of significant liver disease
- b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤ 1.5 x ULN
Troponin I < 2 x ULN
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 in a row, ST elevation consistent with ischemia)

Exclusion criteria

Typical vaccinia scar
Known or suspected history of smallpox vaccination
History of vaccination with any poxvirus-based vaccine
US Military service prior to 1991 or after January 2003
Pregnant or breast-feeding women
Uncontrolled serious infection, i.e. not responding to antimicrobial therapy
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
History of or active autoimmune disease, persons with vitiligo or thyroid disease taking thyroid replacement are not excluded
Known or suspected impairment of immunologic function including, but not limited to, HIV Infection, clinically significant liver disease (including chronic active HBV or HCV), diabetes mellitus, moderate to severe kidney impairment
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
History or clinical manifestation of clinically significant and severe hematological, pulmonary, central nervous, cardiovascular or gastrointestinal disorders
Clinically significant mental disorder not adequately controlled by medical treatment
History of coronary heart disease, myocardial infarction, angina pectoris, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, uncontrolled high blood pressure, or any other heart condition under the care of a doctor
Known history of an immediate family member (father, mother, brother, or sister) who has had onset of ischemic heart disease before age 50 years
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?usertype=prof) NOTE: This criterion applies only to subjects 20 years of age and older
Active or history of chronic alcohol abuse and/or intravenous and/or nasal drug abuse (within the past 6 months)
Known allergy to IMVAMUNE® vaccine and its constituents, e.g. tris (hydroxymethyl)-amino methane, including know allergy to egg or aminoglycosides
History of anaphylaxis or severe allergic reaction to any vaccine
Acute disease (illness with or without a fever) at the time enrollment
Body temperature ≥100.4°F (≥38.0°C) at the time of enrollment
Having received any vaccinations or planned vaccinations with a live vaccine within 30 days prior to or after trial vaccination
Having received any vaccinations or planned vaccinations with a killed vaccine within 14 days prior to or after trial vaccination
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 (V5)
Post organ transplant subjects whether or not receiving chronic immunosuppressive therapy
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 (V5)
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
Trial personnel

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 2	IMVAMUNE®	Two vaccinations four weeks apart (at Day 0 and Day 28) with IMVAMUNE® Lot #2
Group 1	IMVAMUNE®	Two vaccinations four weeks apart (at Day 0 and Day 28) with IMVAMUNE® Lot #1
Group 3	IMVAMUNE®	Two vaccinations four weeks apart (at Day 0 and Day 28) with IMVAMUNE® Lot #3
Group 4	Placebo	Two vaccinations four weeks apart (at Day 0 and Day 28) with 0.5 ml Placebo, Tris-buffered saline (TBS)

Primary Outcome Measures

Name	Time	Method
PRNT GMT	2 weeks following the second vaccination	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'.

Secondary Outcome Measures

Name	Time	Method
ELISA GMT	2 weeks following the second vaccination	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'.
Serious Adverse Events	within 30 weeks	Incidence, relationship and intensity of any Serious Adverse Event (SAE)
Unsolicited Non-serious AEs: Intensity	within 29 days after any vaccination	Occurrence of unsolicited non-serious AEs by Intensity
ELISA Seroconversion Rate	2 weeks following the second vaccination	Seroconversion rate based on 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.
Solicited Local AEs	within 8 days after any vaccination	Incidence and intensity of solicited local AEs (redness, swelling, induration, pruritus and pain). Percentages based on subjects with at least one completed diary card.
PRNT Seroconversion Rate	2 weeks following the second vaccination	Seroconversion rate based on 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.
Correlation PRNT vs ELISA Titers	2 weeks following the second vaccination	Pearson Correlation Coefficient between the log10 transformed PRNT titers and the log10 transformed ELISA titers
Cardiac Signs or Symptoms	within 30 weeks	Incidence, relationship and intensity of any cardiac sign or symptom indicating a case of myo-/pericarditis (Adverse Event of Special Interest (AESI)). An AESI was defined in this trial as: * Any cardiac sign or symptom developed since the first vaccination * ECG changes determined to be clinically significant * Cardiac enzyme Troponin I \>= 2 x ULN (\>= Grade 2)
Related Grade >=3 Adverse Events	within 29 days after any vaccination	Incidence of any Grade \>=3 Adverse Events probably, possibly or definitely related to the trial vaccine. Pooled solicited (general only) and unsolicited AEs
Unsolicited Non-serious AEs: Relationship to Vaccination	within 29 days after any vaccination	Occurrence of unsolicited non-serious AEs by relationship to study vaccine
Solicited General AEs	within 8 days after any vaccination	Incidence of solicited general AEs (pyrexia, headache, myalgia, chills, nausea, and fatigue): Intensity and relationship to vaccination. Percentages based on subjects with at least one completed diary card.

Trial Locations

Locations (33): National Research Institute
🇺🇸
Los Angeles, California, United States
Anaheim Clinical Trials
🇺🇸
Anaheim, California, United States
Northern California Clinical Research Center (NCCRC)
🇺🇸
Redding, California, United States
Tanner Clinic
🇺🇸
Layton, Utah, United States
Advanced Clinical Research, Inc.
🇺🇸
Meridian, Idaho, United States
Accelovance Peoria
🇺🇸
Peoria, Illinois, United States
Benchmark Research
🇺🇸
Fort Worth, Texas, United States
Holston Medical Group
🇺🇸
Bristol, Tennessee, United States
Avail Clinical Research, LLC
🇺🇸
DeLand, Florida, United States
Lynn Institute of the Rockies
🇺🇸
Colorado Springs, Colorado, United States
Southeast Regional Research Group
🇺🇸
Savannah, Georgia, United States
Broward Research Group
🇺🇸
Hollywood, Florida, United States
QPS Bio-Kinetic
🇺🇸
Springfield, Missouri, United States
Heartland Research Associates
🇺🇸
Augusta, Kansas, United States
Clinical Research Center of Nevada, LLC
🇺🇸
Las Vegas, Nevada, United States
Heartland Research Associates, LLC
🇺🇸
Wichita, Kansas, United States
Rochester Clinical Research, Inc.
🇺🇸
Rochester, New York, United States
Rapid Medical Research, Inc.
🇺🇸
Cleveland, Ohio, United States
Omega Medical Research
🇺🇸
Warwick, Rhode Island, United States
PMG Research of Charleston
🇺🇸
Mount Pleasant, South Carolina, United States
Volunteer Research Group
🇺🇸
Knoxville, Tennessee, United States
Advanced Clinical Research
🇺🇸
West Jordan, Utah, United States
Clinical Research Associates of Tidewater
🇺🇸
Norfolk, Virginia, United States
University Physicians Internal Medicine University Physicians & Surgeons, Inc.
🇺🇸
Huntington, West Virginia, United States
Wake Research Associates
🇺🇸
Raleigh, North Carolina, United States
Accelovance Melbourne
🇺🇸
Melbourne, Florida, United States
Washington University in St. Louis, School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Alabama Vaccine Research Clinic
🇺🇸
Birmingham, Alabama, United States
Therapeutics Clinical Research
🇺🇸
San Diego, California, United States
Meridian Clinical Research, LLC
🇺🇸
Omaha, Nebraska, United States
Lynn Health Science Institute
🇺🇸
Oklahoma City, Oklahoma, United States
Columbia Research Group, Inc.
🇺🇸
Portland, Oregon, United States
Family Practice Center of Wooster
🇺🇸
Wooster, Ohio, United States