High Dose IMVAMUNE® in Vaccinia-Naive Individuals

Comparison of Safety and Immunogenicity of a High Dose (5 x 10^8 TCID50) and a Standard Dose (1 x 10^8 TCID50) of IMVAMUNE® in Healthy Vaccinia-Naive Individuals

The purpose of this research is to compare the ability of a new investigational smallpox vaccine called IMVAMUNE® to produce a strong immune response against smallpox disease if given as one single, higher dose compared with two lower doses given one month apart. Another purpose of the study is to see how quickly someone might be protected against smallpox. Volunteers will be vaccinia-naïve adults age 18 and older (born after 1971) divided into 2 groups. Volunteers in Group A will receive a high dose of vaccine given in 2 shots on day 0 followed by a placebo (inactive substance) shot on day 28. Group B will receive the standard dose of vaccine and placebo given in 2 shots on day 0 followed by a standard dose shot on Day 28. Study participation will include 10 planned study visits over approximately 7 months.

Study Overview

• Status: Completed
• Conditions: Smallpox
• Intervention / Treatment: Biological: MVA Smallpox Vaccine; Other: Placebo

Detailed Description

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. As a consequence, there is an urgent need for a safe and efficacious vaccine to protect the public against smallpox. To date, the majority of clinical studies with Modified Vaccinia Ankara (MVA) have studied a prime-boost vaccination regimen, with a dose of up to 1×10^8 tissue culture infectious dose 50 (TCID50) of MVA administered on Days 0 and 28. While this vaccination regimen induces a robust immune response that is protective in a variety of animal models and is appropriate for a pre-smallpox release scenario, in the event of a confirmed release of smallpox, a more rapid vaccination regimen that provides a protective immune response would be desirable. Ideally, at least short-term protection could be obtained with a single dose of vaccine. While a single dose of MVA at 1×10^8 TCID50, does induce an immune response in the majority of recipients, it is possible that a higher dose of MVA could provide a more rapid and/or stronger immune response relative to a single, standard 1×10^8 TCID50 dose of MVA. The goal of this study is to examine the kinetics and magnitude of the immune response of a single high dose of MVA (5×10^8 TCID50) relative to both a single and prime/boost regimen using the standard doses (1×10^8 TCID50) of MVA. This study will complement a current, ongoing study, DMID Protocol 06-0012, which is examining the immune response to compressed prime/boost dosing regimens of MVA administered at (1×10^8 TCID50). Upon the completion of these studies, clinical data will be generated which will inform policy makers about different options for post-event utilization of available smallpox vaccines. The study is designed as a randomized, non-placebo controlled, double blinded study containing two arms: Group A (N=45) will receive a single high dose of IMVAMUNE® (5x10^8 TCID50, consisting of two 0.5 mL injections) vaccine on Day 0 and a single saline placebo dose (single 0.5 mL injection) on Day 28 to match the two dose regimen of Group B. Group B (N=45) will receive a standard two dose regimen of IMVAMUNE® (1x10^8 TCID50) vaccine on Day 0 (consisting of 0.5 mL injection of vaccine and 0.5 mL injection of saline placebo) and Day 28 (single 0.5 mL injection of vaccine). Safety will be measured by assessment of adverse events for 28 days following the last vaccination (56 days following the initial vaccination for those subjects that fail to receive the second dose) and for serious adverse events at six months post the final vaccination, and reactogenicity to the vaccines for 15 days following each vaccination. Immunogenicity testing will include antibody testing [enzyme linked immunosorbent assay (ELISA) and plaque reduction neutralizing antibody titers (PRNT)] and cellular immune responses [(INF-gamma enzyme linked immunospot (ELISPOT)] following each vaccination and at six months post the final vaccination. In addition, ELISA responses, using MVA VR-1508 as the target antigen and PRNT using vaccinia WR (Western Reserve) as the target antigen will be explored. Participants will include 90 healthy, vaccinia-naïve adults, aged 18 and older (born after 1971). Study duration will be approximately 13 months (7 months/subject).

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242-2600
      • University of Iowa - Vaccine Research and Education Unit
  • Missouri
    • Saint Louis, Missouri, United States, 63104-1015
      • Saint Louis University Center for Vaccine Development

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 38 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Prior to initial vaccination: -At least 18 years of age and born after 1971 -Read, sign, and date informed consent document -Available for follow-up for the planned duration of the study (six 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 a. A woman is considered of childbearing potential unless post-menopausal (> 1 year) or surgically sterilized (tubal ligation, bilateral oophorectomy, or hysterectomy) b. 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. -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+ 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 two premature ventricular contractions (PVC's) in a row, or sympathetic tonus (ST) elevation consistent with ischemia] -The following blood parameters: a. Hemoglobin equal or above the lower limit of institutional normal (sex specific); b. White blood cells greater than 2,500 and less than 11,000/mm^3; c. 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 -ECG (obtained after Day 14 after first vaccination) in absence of clinical significance (e.g., complete left or right bundle branch block, incomplete left bundle branch block or sustained ventricular arrhythmia, or two PVC's in a row, or ST elevation consistent with ischemia) -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 a. A woman is considered of childbearing potential unless post-menopausal or surgically sterilized b. 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, and abstinence from sexual intercourse with men (vaginal penetration by a penis, coitus)

Exclusion Criteria:

Exclusion criteria that apply prior to the initial vaccination: -History of immunodeficiency -Typical vaccinia scar -Known or suspected history of smallpox vaccination including Modified Vaccinia Ankara (MVA) alone or as a vector as well as other investigational smallpox vaccine -Military service prior to 1991 or after January 2003 -Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease, diabetes mellitus, or moderate to severe kidney impairment -Malignancy not including squamous cell skin cancer or basal cell skin cancer unless at the vaccination site or history of skin cancer at the vaccination site -Active autoimmune disease a. Persons with vitiligo or thyroid disease (e.g., taking thyroid hormone replacement) are not excluded -History of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, or other heart condition under the care of a doctor -Systolic blood pressure >/= 150 mmHg or diastolic blood pressure >/= 100 mmHg. -Ten percent or greater risk of developing a myocardial infarction or coronary death within the next 10 years using the National Cholesterol Education Program's risk assessment tool (http://hin.nhlbi.nih.gov/atpiii/calculator.asp) NOTE that this criterion applies only to subjects 20 years of age and older and only if at least one of the following apply: a. Have smoked a cigarette in the past month, and/or b. Have hypertension (defined as systolic blood pressure >140 mm Hg) or are on antihypertensive medication, and/or c. Have a family history of coronary heart disease in male first-degree relative (father or brother) <55 years of age or a female first-degree relative (mother or sister) <65 years of age. -High-dose steroid use for greater than 2 weeks duration within three months prior to vaccination and current use of immunosuppressive medication. a. Corticosteroid nasal sprays are permissible b. Persons who are using a topical steroid can be enrolled after their therapy is completed c. Inhaled steroids for asthma are not permissible -Medical or psychiatric condition or occupational responsibilities that preclude subject compliance with the protocol -Any history of illegal injection drug use -Receipt or planned receipt of inactivated vaccine from 14 days prior to the first vaccination through 14 days post second vaccination -Receipt or planned receipt of any other live attenuated vaccine within 30 days prior to the first vaccination through 30 days post second vaccination -Use of any other experimental agent within 30 days prior to vaccination and for the duration of the study -Receipt of blood products or immunoglobulin within six months prior to vaccination -Donation of a unit of blood within 56 days prior to vaccination or prior to Visit 9 -Acute febrile illness (greater than or equal to 100.5 degrees Fahrenheit) on the day of vaccination -Pregnant or lactating women -Eczema of any degree or history of eczema -People with active atopic dermatitis, active exfoliative skin disorders/conditions, current Varicella zoster, or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2×2 cm -Any condition that, in the opinion of the investigator, might interfere with study objectives -Known allergy to IMVAMUNE® vaccine -Known allergy to egg or aminoglycoside (including gentamicin) -Study personnel Exclusion criteria that apply prior to the second vaccination: -History of immunodeficiency -Known or suspected impairment of immunologic function including, but not limited to, clinically sig nificant liver disease, diabetes mellitus, or moderate to severe kidney impairment -Malignancy not including squamous cell skin cancer or basal cell skin cancer unless at the vaccination site or history of skin cancer at the vaccination site -Active autoimmune disease a. Persons with vitiligo or thyroid disease (e.g., taking thyroid hormone replacement) are not excluded -History of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, or other heart condition under the care of a doctor -Systolic blood pressure >/= 150 mmHg or diastolic blood pressure >/=100 mmHg -High-dose steroid use for greater than 2 weeks duration within three months prior to vaccination and current use of immunosuppressive medication. a. Corticosteroid nasal sprays are permissible b. Persons who are using a topical steroid can be enrolled after their therapy is completed c. Inhaled steroids for asthma are not permissible -Medical or psychiatric condition or occupational responsibilities that preclude subject compliance with the protocol -Any history of illegal injection drug use -Receipt or planned receipt of inactivated vaccine from 14 days prior to vaccination through 14 days post second vaccination -Receipt or planned receipt of any other live attenuated vaccine from 30 days prior to vaccination through 30 days post second vaccination -Use of any other experimental agent within 30 days prior to vaccination and for the duration of the study -Receipt of blood products or immunoglobulin within six months prior to vaccination -Donation of a unit of blood within 56 days prior to vaccination or prior to Visit 9 -Acute febrile illness (greater than or equal to 100.4 degrees Fahrenheit) on the day of vaccination -Pregnant or lactating women -Eczema of any degree or history of eczema -People with active atopic dermatitis, active exfoliative skin disorders/conditions, current Varicella zoster, or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2×2 cm -Any condition that, in the opinion of the investigator, might interfere with study objectives -Known allergy to IMVAMUNE® vaccine -Known allergy to egg or aminoglycoside (including gentamicin)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: High Dose; Single high dose of IMVAMUNE® (5x10^8 TCID50, consisting of two 0.5 mL injections) vaccine on Day 0 and a single saline placebo dose (single 0.5 mL injection) on Day 28 to match the two dose regimen of Group B.	Biological: MVA Smallpox Vaccine; IMVAMUNE® Vaccinia Vaccine, undiluted, delivered by subcutaneous route on Day 0 at high dose 5×10^8 TCID50 (5×10^8 TCID50 per 1.0 mL dose - administered as 2 x 0.5 mL.; Other: Placebo; 0.5 mL injection of saline placebo administered with vaccine on Day 0 (Group B) or single saline placebo dose (single 0.5 mL injection) on Day 28 (Group A).
Active Comparator: Group B: Standard Dose; Standard two dose regimen of IMVAMUNE® (1x10^8 TCID50) vaccine on Day 0 (consisting of 0.5 mL injection of vaccine and 0.5 mL injection of saline placebo) and Day 28 (single 0.5 mL injection of vaccine).	Biological: MVA Smallpox Vaccine; IMVAMUNE® Vaccinia Vaccine, undiluted, delivered by subcutaneous route on Day 0 at high dose 5×10^8 TCID50 (5×10^8 TCID50 per 1.0 mL dose - administered as 2 x 0.5 mL.; Other: Placebo; 0.5 mL injection of saline placebo administered with vaccine on Day 0 (Group B) or single saline placebo dose (single 0.5 mL injection) on Day 28 (Group A).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Seroconversion After One Vaccination Using Bavarian Nordic's (BN) Enzyme Linked Immunosorbent Assay (ELISA) in the Intent-to-Treat (ITT) Population	Seroconversion is defined as a titer >= 50 or as a 2-fold or greater increase in titer from baseline if pre-vaccination titer was >= 50. Participants who did not seroconvert during the study were analyzed as right censored at the last sample collection date. Samples collected after the second vaccination were also analyzed as right censored.	Days 0, 4, 8, 14, 21, and 28 after first vaccination
Time to Seroconversion After One Vaccination Using BN ELISA in the Per Protocol Population	Seroconversion is defined as a titer >= 50 or as a 2-fold or greater increase in titer from baseline if pre-vaccination titer was >= 50. Participants who did not seroconvert during the study were analyzed as right censored at the last sample collection date. Samples collected after the second vaccination were also analyzed as right censored.	Days 0, 4, 8, 14, 21, and 28 after first vaccination
Frequency of Serious Adverse Events (SAEs) Related to Vaccination	The number of participants who experienced at least one SAE throughout the course of the study that was deemed related to the study vaccination. A SAE is defined as an AE meeting one of the following conditions: Death during the study period (from first vaccine until end of surveillance period); Life-threatening (defined as a participant at immediate risk of death at the time of the event); Requires inpatient hospitalization or prolongation of existing hospitalization during the period of protocol-defined surveillance; Results in a congenital anomaly or birth defect; Results in a persistent or significant disability/incapacity; Severe adverse event associated with study product	Day 0 after first vaccination to study completion through Day 180 after second vaccination (Day 208 after first vaccination)
Frequency of Non-Serious AEs Related to Vaccination	The number of participants who experienced at least one unsolicited non-serious AE of any severity from Day 0 to 28 days post second vaccination (56 days post first vaccination) that was deemed related to the study vaccination.	Day 0 after first vaccination to Day 28 after second vaccination (Day 56 after first vaccination)
Frequency of Local Solicited Reactogenicity AEs for Subjective Symptoms	Local solicited reactogenicity AEs were collected daily for 15 days post each vaccination using a memory aid. Local subjective events included pain at injection site, itchiness at injection site, underarm pain, and underarm swelling and were graded on a scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe).	Day 0 through Day 15 after first vaccination; Day 0 through Day 15 after second vaccination (Day 28 through Day 43 after first vaccination)
Frequency of Local Solicited Reactogenicity AEs for Measured Symptoms	Local solicited reactogenicity AEs were collected daily for 15 days post each vaccination using a memory aid. Local measured events included erythema and induration at the vaccination site and were measured in millimeters.	Day 0 through Day 15 after first vaccination; Day 0 through Day 15 after second vaccination (Day 28 through Day 43 after first vaccination)
Frequency of Systemic Solicited Reactogenicity AEs	Systemic solicited reactogenicity AEs were collected daily for 15 days post each vaccination using a memory aid. Systemic events included muscle aches, chills, headache, nausea, feeling tired, change in appetite, joint pain, and elevated oral temperature. Events were graded on a scale of Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate), and Grade 3 (Severe).	Day 0 through Day 15 after first vaccination; Day 0 through Day 15 after second vaccination (Day 28 through Day 43 after first vaccination)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Titer of Saint Louis University's (SLU) Plaque Reduction Neutralizing Antibody Titer (PRNT) Assay After First Vaccination in the ITT Population	The peak PRNT is defined as the largest titer among all available measurements post-first vaccination but prior to the second vaccination. Means and corresponding standard errors are calculated on the log2.5 scale.	Days 4, 8, 14, 21, and 28 after first vaccination
Peak Titer of SLU PRNT Assay After First Vaccination in the Per Protocol Population	The peak PRNT is defined as the largest titer among all available measurements post-first vaccination but prior to the second vaccination. Means and corresponding standard errors are calculated on the log2.5 scale.	Days 4, 8, 14, 21, and 28 after first vaccination

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2009
• Primary Completion (Actual): March 9, 2011
• Study Completion (Actual): March 9, 2011

Study Registration Dates

• First Submitted: April 9, 2009
• First Submitted That Met QC Criteria: April 9, 2009
• First Posted (Estimated): April 10, 2009

Study Record Updates

• Last Update Posted (Actual): June 13, 2025
• Last Update Submitted That Met QC Criteria: June 12, 2025
• Last Verified: January 26, 2012

More Information

Terms related to this study

• Keywords: vaccine; smallpox; IMVAMUNE®
• Additional Relevant MeSH Terms: Infections; Virus Diseases; Poxviridae Infections; DNA Virus Infections; Smallpox; Vaccinia
• Other Study ID Numbers: 08-0040; N01AI80003C; POX-MVA-028

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No