SmallpoxPhase 2NCT00914732

Lyophilized IMVAMUNE® (1x10^8 TCID50) Versus Liquid IMVAMUNE® (1x10^8 TCID50) Administered Subcutaneously and a Lower Dose Liquid IMVAMUNE® (2x10^7 TCID50) Administered Intradermally

A Phase 2 study testing MVA Smallpox Vaccine in people with Smallpox, run by National Institute of Allergy and Infectious Diseases (NIAID) at 8 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 38 yearsHealthy volunteers can take part
Conditions the study is for: Smallpox
What is being tested?: MVA Smallpox Vaccine
Type of treatment: Vaccines, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 523 participants
Where: 8 sitesUnited States
Study dates: Feb 2010to Apr 2011
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 38 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

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.

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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 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).
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:
Hemoglobin equal or above the lower limit of institutional normal (sex-specific);
White blood cells greater than 2,500 and less than 11,000/mm^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:
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).
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.

Who cannot join

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

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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
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 greater than or equal to 150 mmHg or diastolic blood pressure greater than or equal to 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://hp2010.nhlbihin.net/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:
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
Corticosteroid nasal sprays are permissible
Persons who are using a topical steroid can be enrolled after their therapy is completed
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 and prior to Visit 6
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
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:
Continued inflammation (erythema and/or induration) graded as moderate or severe at the site of the initial vaccination
History of immunodeficiency
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
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 greater than or equal to 150 mmHg or diastolic blood pressure greater than or equal to 100 mmHg
High-dose steroid use for greater than 2 weeks duration within three months prior to vaccination and current use of immunosuppressive medication.
Corticosteroid nasal sprays are permissible
Persons who are using a topical steroid can be enrolled after their therapy is completed
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 of or planned receipt of inactivated vaccine from 14 days prior to vaccination through 14 days post second vaccination
Receipt of 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 and prior to Visit 6
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
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)

Trial locations and contacts

8 sites in 1 country.

City, postcode or hospital

8 sites in 1 country

United States8 sites

University of Maryland School of Medicine - Center for Vaccine Development - Baltimore
Baltimore, Maryland, 21201-1509
Emory Vaccine Center - The Hope Clinic
Decatur, Georgia, 30030-1705
Baylor College of Medicine - Molecular Virology and Microbiology
Houston, Texas, 77030-3411
University of Iowa - Vaccine Research & Education Unit
Iowa City, Iowa, 52242-2600
Vanderbilt University Hospital - Pediatric Clinical Research
Nashville, Tennessee, 37232-0004
Group Health Research Institute - Seattle
Seattle, Washington, 98101-1466
The University of Washington - Virology Research Clinic
Seattle, Washington, 98104-2433
Saint Louis University - Center for Vaccine Development
St Louis, Missouri, 63104-1015

Other trials in United States

About this study

Official title: Comparison of the Safety and Immunogenicity of Lyophilized IMVAMUNE® (1x10^8 TCID50) Versus Liquid Formulation IMVAMUNE® (1x10^8 TCID50) Administered by the Subcutaneous Route and a Lower Dose Liquid Formulation IMVAMUNE® (2x10^7 TCID50) Administered by the Intradermal Route in Healthy Vaccinia-Naïve Individuals

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.

Read the 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.

Conditions: Smallpox
Being tested: MVA Smallpox Vaccine
Keywords: IMVAMUNE®, smallpox, vaccine
Medical subject headings: Smallpox

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

MVA Smallpox VaccineBiological
Vaccinia vaccine liquid formulation delivered by subcutaneous (SC) route at 1x10^8 TCID50 per 0.5 mL dose on Days 0 and 28.
MVA Smallpox VaccineBiological
Vaccinia vaccine liquid formulation delivered at lower dose [2x10^7 tissue culture infectious dose 50 (TCID50) per 0.1 mL dose] by intradermal (ID) route on Days 0 and 28.
MVA Smallpox VaccineBiological
Vaccinia vaccine lyophilized formulation delivered by subcutaneous (SC) route at 1x10^8 TCID50 per 0.5 mL dose on Days 0 and 28.

Study groups in NCT00914732
Study group	Role	What they receive
Group B, liquid, subcutaneous	Experimental	Group B: 165 subjects will 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. Receives: Biological: MVA Smallpox Vaccine
Group C, liquid, intradermal	Experimental	Group C: 165 subjects will 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. Receives: Biological: MVA Smallpox Vaccine
Group A, lyophilized, subcutaneous	Experimental	Group A: 165 subjects will 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. Receives: Biological: MVA Smallpox Vaccine

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: Days 14, 28 and 180 after 2nd vaccination
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.
Measured: Days 14, 28 and 180 after 2nd vaccination
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.
Measured: Days 14, 28 and 180 after 2nd vaccination
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.
Measured: Days 14, 28 and 180 after 2nd vaccination
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.
Measured: Day 0 through 180 days after second vaccination

Secondary outcomes (5)

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.
Measured: Days 0, 14 and 42
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.
Measured: Days 14, 28 and 180 after 2nd vaccination
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.
Measured: Days 14, 28 and 180 after second vaccination
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.
Measured: Days 14, 28 and 180 after 2nd vaccination.
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.
Measured: Days 14, 28 and 180 after 2nd vaccination.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Feb 2010Apr 2011

First posted5 Jun 2009 (estimated)
Study startFeb 2010
Primary completionApr 2011
Study completionApr 2011

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for SmallpoxStudies of the same condition, open and under way.
More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Investigator, Outcomes assessor
Enrolment: 523 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00914732
Sponsor's protocol ID: 09-0002
Other IDs: POX-MVA-029
Status last verified: Jan 2011
First submitted: 4 Jun 2009
Last updated: 3 Feb 2021
Results posted: Yes, on ClinicalTrials.gov

Publications

Frey SE, Stapleton JT, Ballas ZK, Rasmussen WL, Kaufman TM, Blevins TP, Jensen TL, Davies DH, Tary-Lehmann M, Chaplin P, Hill H, Goll JB; DMID 09-0002 MVA Vaccine Study Group. Human Antibody Responses Following Vaccinia Immunization Using Protein Microarrays and Correlation With Cell-Mediated Immunity and Antibody-Dependent Cellular Cytotoxicity Responses. J Infect Dis. 2021 Oct 28;224(8):1372-1382. doi: 10.1093/infdis/jiab111.
PubMed 33675226

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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All Smallpox trials

Study at a glance

From the registry record, last updated by the sponsor on 3 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Comparison of the Safety and Immunogenicity of Lyophilized IMVAMUNE® (1x10^8 TCID50) Versus Liquid Formulation IMVAMUNE® (1x10^8 TCID50) Administered by the Subcutaneous Route and a Lower Dose Liquid Formulation IMVAMUNE® (2x10^7 TCID50) Administered by the Intradermal Route in Healthy Vaccinia-Naïve Individuals
ClinicalTrials.gov ID: NCT00914732
Acronym / sponsor ID: 09-0002
Conditions: Smallpox
Keywords: IMVAMUNE®, smallpox, vaccine
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 523 participants (actual)
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
Study start: Feb 2010
Primary completion: Apr 2011 (actual)
Study completion: Apr 2011 (actual)
First posted: 5 Jun 2009 (estimated)
Results: Posted 12 Jan 2021

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (participant, investigator, outcomes assessor)
Number of arms: 3

Arm	Type	Receives
Group B, liquid, subcutaneous	Experimental	Biological: MVA Smallpox VaccineGroup B: 165 subjects will 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.
Group C, liquid, intradermal	Experimental	Biological: MVA Smallpox VaccineGroup C: 165 subjects will 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.
Group A, lyophilized, subcutaneous	Experimental	Biological: MVA Smallpox VaccineGroup A: 165 subjects will 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.

Who may qualify

Ages: 18 to 38 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (26 listed)

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.

Key exclusion criteria (60 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
MVA Smallpox VaccineVaccinia vaccine liquid formulation delivered by subcutaneous (SC) route at 1x10^8 TCID50 per 0.5 mL dose on Days 0 and 28.	Biological	Group B, liquid, subcutaneous
MVA Smallpox VaccineVaccinia vaccine liquid formulation delivered at lower dose [2x10^7 tissue culture infectious dose 50 (TCID50) per 0.1 mL dose] by intradermal (ID) route on Days 0 and 28.	Biological	Group C, liquid, intradermal
MVA Smallpox VaccineVaccinia vaccine lyophilized formulation delivered by subcutaneous (SC) route at 1x10^8 TCID50 per 0.5 mL dose on Days 0 and 28.	Biological	Group A, lyophilized, subcutaneous

Primary outcome

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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Number of Participants Reporting Serious Adverse Events Associated With IMVAMUNE® Vaccination
Time frame: 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.

5 secondary outcomes

Number of Participants Assessed With Grade 3 and 4 Laboratory Toxicities Associated With IMVAMUNE®.
Time frame: Days 0, 14 and 42
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
Time frame: Days 14, 28 and 180 after 2nd vaccination
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
Time frame: Days 14, 28 and 180 after second vaccination
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.
Time frame: Days 14, 28 and 180 after 2nd vaccination.
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.
Time frame: Days 14, 28 and 180 after 2nd vaccination.

Results and safety

Results posted to the registry on 12 Jan 2021, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Lyophilized, Subcutaneous	165	155
Liquid, Subcutaneous	167	160
Liquid, Intradermal	191	180

Primary outcome: 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

Time frame: Days 14, 28 and 180 after 2nd vaccination. Geometric mean (95% Confidence Interval). Unit: titer

Measure	Lyophilized, Subcutaneous n = 161	Liquid, Subcutaneous n = 164
Value	77.9 (62.9 to 96.5)	46.7 (37.9 to 57.4)

Lyophilized, Subcutaneous vs Liquid, Subcutaneous: Mean Difference (Final Values): -0.74 (97.5% CI -1.23 to -0.25)

Population analysed: 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.

Primary outcome: 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

Time frame: Days 14, 28 and 180 after 2nd vaccination. Geometric mean (95% Confidence Interval). Unit: titer

Measure	Lyophilized, Subcutaneous n = 145	Liquid, Subcutaneous n = 149
Value	87.8 (71.2 to 108.3)	49.5 (40.0 to 61.3)

Lyophilized, Subcutaneous vs Liquid, Subcutaneous: Mean Difference (Final Values): -0.83 (97.5% CI -1.32 to -0.33)

Population analysed: 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.

Primary outcome: 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

Time frame: Days 14, 28 and 180 after 2nd vaccination. Geometric mean (95% Confidence Interval). Unit: titer

Measure	Liquid, Intradermal n = 187	Liquid, Subcutaneous n = 164
Value	45.2 (37.0 to 55.4)	46.7 (37.9 to 57.4)

Liquid, Intradermal vs Liquid, Subcutaneous: Mean Difference (Final Values): 0.05 (97.5% CI -0.43 to 0.52)

Primary outcome: 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

Time frame: Days 14, 28 and 180 after 2nd vaccination. Geometric mean (95% Confidence Interval). Unit: titer

Measure	Liquid, Intradermal n = 146	Liquid, Subcutaneous n = 149
Value	59.6 (48.1 to 74.0)	49.5 (40.0 to 61.3)

Liquid, Intradermal vs Liquid, Subcutaneous: Mean Difference (Final Values): -0.27 (97.5% CI -0.77 to 0.23)

5 secondary outcomes are reported in the full results.

Adverse events

Time frame: Solicited reactogenicity symptoms were collected on memory aid for 15 days after each vaccination. Non-serious unsolicited adverse events were collected for 28 days after each vaccination. Serious adverse events were collected through 180 days after the second vaccination.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Lyophilized, Subcutaneous	1 of 165 (0.6%)	164 of 165 (99.4%)	0 of 165
Liquid, Subcutaneous	2 of 167 (1.2%)	161 of 167 (96.4%)	0 of 167
Liquid, Intradermal	1 of 191 (0.5%)	191 of 191 (100%)	0 of 191

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 3 Feb 2021.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 33675226Frey SE, Stapleton JT, Ballas ZK, Rasmussen WL, Kaufman TM, Blevins TP, Jensen TL, Davies DH, Tary-Lehmann M, Chaplin P, Hill H, Goll JB; DMID 09-0002 MVA Vaccine Study Group. Human Antibody Responses Following Vaccinia Immunization Using Protein Microarrays and Correlation With Cell-Mediated Immunity and Antibody-Dependent Cellular Cytotoxicity Responses. J Infect Dis. 2021 Oct 28;224(8):1372-1382. doi: 10.1093/infdis/jiab111.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

8 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing MVA Smallpox Vaccine in people with Smallpox, run by National Institute of Allergy and Infectious Diseases (NIAID) at 8 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 60 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Jan 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: Days 14, 28 and 180 after 2nd vaccination). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00914732, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Feb 2021.