A Randomized, Double-blind, Placebo-controlled Study on Immunogenicity and Safety of MVA-BN (IMVAMUNE™) Smallpox Vaccine in Healthy Subjects

A Partially Randomized, Partially Double-blind, Placebo-controlled Phase II Non-inferiority Study to Evaluate Immunogenicity and Safety of One and Two Doses of MVA-BN® (IMVAMUNE™) Smallpox Vaccine in 18-55 Year Old Healthy Subjects

The primary objective of this study is to evaluate the immune response after a single vaccination of pre-immune subjects compared to two vaccinations in naive subjects.

In addition the study further investigates the cardiac safety profile of MVA-BN® in a healthy population compared to placebo.

Study Overview

• Status: Completed
• Conditions: Smallpox
• Intervention / Treatment: Biological: MVA-BN® (IMVAMUNE); Biological: Placebo

Detailed Description

The study consists of 4 groups, which receive either MVA-BN once, MVA-BN two times, MVA-BN followed by placebo, or two administrations of placebo.

• Study Type: Interventional
• Enrollment (Actual): 745
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Bavaria
    • Munich, Bavaria, Germany, 80636
      • Harrison Clinical Research GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male and female subjects between 18 and 55 years of age.
2. Women must have a negative serum pregnancy test at screening and a negative urine or serum pregnancy test within 24 hours prior to vaccination.
3. Women of childbearing potential 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 study, and must not become pregnant for at least 28 days after the last vaccination. A woman is considered of childbearing potential unless post-menopausal or surgically sterilized. (Acceptable contraception methods are restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products.)
4. Lab values without clinically significant findings
5. Electrocardiogram (ECG) without abnormal 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, 2 premature ventricular contractions (PVC) in a row, ST elevation consistent with ischemia).

Groups 1, 2 and 3 (All vaccinia-naïve subjects) additionally:

1. No history of known or suspected previous smallpox vaccination.
2. No detectable vaccinia scar.

Group 4 (All previously vaccinated subjects) additionally:

1. History of previous smallpox vaccination (documented and/or typical vaccinia scar).
2. Most recent smallpox vaccination ≥ 5 years.

Exclusion Criteria:

1. Uncontrolled serious infection i.e. not responding to antimicrobial therapy.
2. History of or active autoimmune disease. Persons with vitiligo or thyroid disease taking thyroid replacement are not excluded.
3. Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease; diabetes mellitus; moderate to severe kidney impairment.
4. 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 at the vaccination site are excluded.
5. 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.
6. History of an immediate family member (father, mother, brother, or sister) who died due to ischemic heart disease before age 50 years.
7. 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 volunteers 20 years of age and older.
8. History of anaphylaxis or severe allergic reaction.
9. Immune modulatory therapy.
10. History of any serious medical condition, which in the opinion of the investigator would compromise the safety of the subject.
11. History or clinical manifestation of clinically significant and severe hematological, renal, hepatic, pulmonary, central nervous, cardiovascular or gastrointestinal disorders.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GP 1: two x 1x10E08 TCID, MVA-BN® s.c., vaccinia naive; vaccinia naive subjects receiving two subcutanenous vaccinations with 0.5ml MVA-BN® IMVAMUNE (1x10E08 TCID)	Biological: MVA-BN® (IMVAMUNE); 1x 10E8_TCID50
Experimental: GP 2: 1x10E08 TCID, MVA-BN®, 1x Placebo, s.c., vaccinia naive; vaccinica naive subjects receiving one vaccination with 0.5ml MVA-BN® IMVAMUNE(1x10E08 TCID), followed by one vaccination Placebo (0.5ml Tris Buffer)	Biological: MVA-BN® (IMVAMUNE); 1x 10E8_TCID50; Biological: Placebo; Tris-Buffer
Placebo Comparator: GP 3: two x Placebo, s.c., vaccinia naive; vaccinia naive subjects, receiving two subcutaneous vaccinations with Placebo (0.5ml Tris Buffer).	Biological: Placebo; Tris-Buffer
Experimental: GP 4: 1x10E08 TCID, MVA-BN®, s.c., vaccinia experienced; vaccinia experienced subjects, receiving one subcutaneous vaccination with 0.5ml MVA-BN® IMVAMUNE (1x10E08 TCID).	Biological: MVA-BN® (IMVAMUNE); 1x 10E8_TCID50

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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. Percentages based on number of subjects with data available.	2 weeks following the last vaccination (Week 6 for Groups 1-3, Week 2 for Group 4)
Number of Participants With ECG Changes	Occurrence of any specific or unspecific ECG change. Assessments at Screening (SCR), Visit 2 (Week 2) and Visit 4 (Week 6).	within 2 weeks after each vaccination
Number of Cardiac Adverse Events (Adverse Events of Special Interest [AESI])	Occurrence and relationship of any other cardiac symptom at any time during the study	within 32 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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. Percentages based on number of subjects with data available.	4 weeks following the last vaccination (Week 8 for Groups 1-3, Week 4 for Group 4)
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 (6) 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.	2 weeks following the last vaccination (Week 6 for Groups 1-3, Week 2 for Group 4)
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 (6) 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.	4 weeks following the last vaccination (Week 8 for Groups 1-3, Week 4 for Group 4)
Number of Participants With Related Serious Adverse Events	Number of participants with any serious adverse event possibly, probably or definitely related to the study vaccine at any time during the study	within 32 weeks
Number of Participants With Solicited Local Adverse Events	Number of participants with solicited local AEs (pain, erythema, swelling and induration) within 8 days after any vaccination (vaccinations for Groups 1-3: Days 0 and 28; Group 4: Day 0). Percentages based on subjects with at least one completed diary card.	within 8 days after any vaccination
Number of Participants With Solicited General Adverse Events	Number of participants with solicited systemic/general AEs (body temperature increased, headache, myalgia, nausea, and fatigue) within 8 days after any vaccination (vaccinations for Groups 1-3: Days 0 and 28; Group 4: Day 0). Percentages based on subjects with at least one completed diary card.	within 8 days after any vaccination
Number of Participants With Related Grade>=3 Adverse Events	Number of participants with any Grade >=3 AE probably, possibly, or definitely related to the study vaccine within 4 weeks after any vaccination (vaccinations for Groups 1-3: Days 0 and 28; Group 4: Day 0). Pooled solicited (local and general) and unsolicited AEs.	within 4 weeks after any vaccination
Number of Participants With Unsolicited Non-serious Adverse Events	Number of participants with non-serious unsolicited AEs within 4 weeks after any vaccination (vaccinations for Groups 1-3: Days 0 and 28; Group 4: Day 0).	within 4 weeks after any vaccination

Collaborators and Investigators

• Sponsor: Bavarian Nordic
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Frank von Sonnenburg, Prof, Section of International Medicine & Public Health, Department of Infectious Diseases and Tropical Medicine, Ludwig-Maximilians Unviersity Munich

Publications and helpful links

General Publications

• Zitzmann-Roth EM, von Sonnenburg F, de la Motte S, Arndtz-Wiedemann N, von Krempelhuber A, Uebler N, Vollmar J, Virgin G, Chaplin P. Cardiac safety of Modified Vaccinia Ankara for vaccination against smallpox in a young, healthy study population. PLoS One. 2015 Apr 16;10(4):e0122653. doi: 10.1371/journal.pone.0122653. eCollection 2015.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2006
• Primary Completion (Actual): February 1, 2007
• Study Completion (Actual): August 1, 2007

Study Registration Dates

• First Submitted: April 19, 2006
• First Submitted That Met QC Criteria: April 19, 2006
• First Posted (Estimate): April 21, 2006

Study Record Updates

• Last Update Posted (Actual): March 6, 2019
• Last Update Submitted That Met QC Criteria: February 11, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Prevention; Vaccination; Smallpox
• Additional Relevant MeSH Terms: Virus Diseases; Infections; DNA Virus Infections; Poxviridae Infections; Smallpox
• Other Study ID Numbers: POX-MVA-005; DMID 05-0128; EudraCT No. 2005-001781-14