Randomized, Open-label Phase II Trial to Assess the Safety and Immunogenicity of MVA-BN Smallpox Vaccine in Immunocompromised Subjects With HIV Infection

Study Overview
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Brief Summary
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The main purpose of this clinical trial is to generate additional safety data in a highly immunocompromised population. HIV-infected persons are considered excellent candidates to represent the highly immunocompromised population for enrolment in this trial. Additionally, the immune system's response (protection against smallpox as measured by the amount of antibodies produced) following injections of MVA-BN® smallpox vaccine will be evaluated. All participants in this trial will be randomly and evenly assigned to one of three groups to receive two, three or four injections. Group 1 will receive the standard regime consisting of one dose at each vaccination time point, Group 2 will receive two doses at each vaccination time point and Group 3 will receive a booster vaccination 12 weeks after the standard vaccination schedule with MVA-BN® smallpox vaccine. Participation in the trial is scheduled to last up to 75 weeks.

Official Title
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Randomized, Open-label Phase II Trial to Assess the Safety and Immunogenicity of MVA-BN Smallpox Vaccine When Increasing the Number of Injections Compared to the Standard Regimen in Immunocompromised Subjects With HIV Infection

Conditions
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Smallpox

Intervention / Treatment
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* Biological: IMVAMUNE®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects aged between 18-45 years, vaccinia-naïve. HIV-1 infection documented by ELISA and confirmed by Western blot at any time prior to study entry. HIV-1 deoxyribonucleic acid (DNA) polymerase chain reaction (PCR), HIV-1 culture, HIV-1 antigen, plasma HIV-1 ribonucleic acid (RNA), or a second antibody test other than ELISA is acceptable as an alternative test at any time prior to study entry. On stable antiretroviral therapy (ART) i.e. Combination ART for at least 6 months. Subject must be on the same ART regimen for at least 12 weeks with no change prior to enrollment in this clinical trial. Screening HIV-1 RNA < 200 copies/ml by US Food and Drug Administration (FDA) approved PCR assay within 45 days prior to study entry. Current CD4 counts ≥ 100 cells/µl ≤ 500 cells/µl. Documented nadir CD4 count < 200 cells/µl at any time prior to enrollment. Hemoglobin ≥ 9.0 g/dl for female subjects, ≥ 10.0 g/dl or male subjects. Platelets ≥ 100,000/mm3. Ability and willingness of subject to provide written informed consent. Body Mass Index (BMI) ≥ 18.5 and < 35 kg/m2. 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 (defined as ≥ 12 months without a menstrual period) or surgically sterilized. 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 (SCR) and a negative urine pregnancy test within 24 hours prior to each vaccination. Absolute neutrophil count cells ≥ 750/mm3. 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: Total bilirubin ≤ 2 x upper limit normal (ULN) in the absence of other evidence of significant liver disease Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤ 2.5 x ULN. Troponin I < 2 x ULN at entry in the clinical trial. 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: Pregnant or breast-feeding women. Typical vaccinia scar. Known or suspected history of smallpox vaccination. History of vaccination with any poxvirus-based vaccine. 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 including uncontrolled diabetes as according to the 'Division of Acquired Immune Deficiency Syndrome (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events' Version 1.0, December 2004, Clarification August 2009. 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 except those defined in the inclusion criteria, including, but not limited to clinically significant liver disease, diabetes mellitus type I and 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 (except HIV infection, chronic or active Hepatitis-B-Virus or Hepatitis-C-Virus infection). Clinically significant psychiatric 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. Current alcohol abuse (40 g/day for at least 6 month) and/or intravenous and/or intranasal drug abuse (within the past 6 months). Known allergy to MVA-BN® vaccine or any of its constituents, e.g. tris (hydroxymethyl)-amino methane, including known 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 of 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. Use of immunosuppressant or immunomodulatory agents including systemic glucocorticoids (excluding nasal or inhaled steroids), tacrolimus, sirolimus, rapamycin, mycophenolate, cyclosporine, TNF-alpha blockers or antagonists, azathioprine, interferon, growth factors, or intravenous immunoglobulin in the 60 days prior to enrollment in this clinical trial. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (standard regimen)<br>One injection at Day 0 and Day 28 with IMVAMUNE® (MVA-BN®) | Biological: IMVAMUNE®<br>* 0.5 ml Modified Vaccinia Ankara Strain - Bavarian Nordic (MVA-BN®) smallpox vaccine containing at least 1 x 10E8 TCID50 per ml<br>* Other names: MVA-BN® smallpox vaccine;|
| Experimental: Group 2 (double dose regimen)<br>Two injections at Day 0 and two injections at Day 28 with IMVAMUNE® (MVA-BN®) | Biological: IMVAMUNE®<br>* 0.5 ml Modified Vaccinia Ankara Strain - Bavarian Nordic (MVA-BN®) smallpox vaccine containing at least 1 x 10E8 TCID50 per ml<br>* Other names: MVA-BN® smallpox vaccine;|
| Experimental: Group 3 (booster regimen)<br>One injection at Day 0 and Day 28 and one booster injection at week 12 with IMVAMUNE® (MVA-BN®) | Biological: IMVAMUNE®<br>* 0.5 ml Modified Vaccinia Ankara Strain - Bavarian Nordic (MVA-BN®) smallpox vaccine containing at least 1 x 10E8 TCID50 per ml<br>* Other names: MVA-BN® smallpox vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With SAEs | Occurrence, relationship and intensity of any serious AE (SAE) | within 75 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With AESIs | Occurrence, relationship to the trial vaccine, and intensity of any adverse event of special interest (AESI) | within 75 weeks | 
| Number of Participants With Related Grade >=3 Adverse Events | Number of Participants with any Grade >=3 Adverse Event probably, possibly, or definitely related to the study vaccine. Pooled solicited and unsolicited AEs. | within 29 days after any vaccination | 
| Number of Unsolicited Non-serious Adverse Events: Relationship to Vaccination | Occurrence of unsolicited non-serious AEs by relationship to study vaccine | within 29 days after any vaccination | 
| Number of Unsolicited Non-serious Adverse Events: Intensity | Occurrence of unsolicited non-serious AEs by Intensity | within 29 days after any vaccination | 
| Number of Participants With Solicited Local Adverse Events | Number of participants with solicited local AEs (redness, swelling, induration, pruritus, and pain) by intensity. Percentages based on subjects with at least one completed diary card. [Injection site erythema, injection site swelling and injection site induration--all sizes measured in diameter with max severity of: 0=0, 1 = <30 mm, 2 = ≥30 - <100 mm, 3 = ≥100 mm. Injection site pruritus: 0=absent, 1=mild, 2=moderate, 3=severe. Injection site pain: 0=absent, 1=painful to touch, 2=painful when limb is moved, 3=spontaneously painful/prevents normal activity.] | within 8 days after any vaccination | 
| Number of Participants With Solicited General AEs | Number of Participants with solicited systemic/general AEs (pyrexia, headache, myalgia, nausea, fatigue, and chills) by intensity. Percentages based on subjects with at least one completed diary card. [Body temperature: 0 = <99.5 F (<37.5 C), 1 = ≥99.5 - <100.4 F (≥37.5 - <38.0 C), 2= ≥100.4 - <102.2 F (≥38.0 - <39.0 C), 3= ≥102.2 - <104.0 F (≥39.0 - <40.0 C), 4= ≥ 104.0 F (≥40.0 C); pyrexia is defined as oral temperature ≥ 100.4 F (≥ 38.0 C).] [Headache, myalgia, nausea, chills and fatigue: 0 = none, 1 = mild: easily tolerated, minimal discomfort and no interference with daily activity, 2 = moderate: some interference with daily activity, 3 = severe: prevents daily activity.] | within 8 days after any vaccination | 
| CD4+ T Cell Counts | Mean CD4+ T-cell counts over time | within 15 days after each vaccination | 
| Geometric Mean Titers (GMT) Measured by Enzyme-linked Immunosorbent Assay (ELISA) at All Immunogenicity Sampling Points | GMTs based on vaccinia-specific ELISA. Titers below the detection limit are included with a value of '1'. | within 64 weeks | 
| ELISA GMT 2 Weeks Following the Second Vaccination (Group 2 Compared to Group 1 and Group 3 (Combined)) | GMTs based on vaccinia-specific ELISA. Titers below the detection limit are included with a value of '1'. | Week 6 | 
| ELISA GMT 2 Weeks Following the Last Vaccination | GMTs based on vaccinia-specific ELISA. Titers below the detection limit are included with a value of '1'. | Week 6 (Groups 1 and 2), Week 14 (Group 3) | 
| ELISA GMT During Follow-up | GMTs based on vaccinia-specific ELISA. Titers below the detection limit are included with a value of '1'. Participants discontinued prior to the follow-up visits are excluded. | Weeks 30 and 56 (Groups 1 and 2), Weeks 38 and 64 (Group 3) | 
| GMTs Measured by Plaque Reduction Neutralization Test (PRNT) at All Immunogenicity Sampling Points | GMTs based on vaccinia-specific PRNT. Titers below the detection limit are included with a value of '1'. | within 64 weeks | 
| PRNT GMT 2 Weeks Following the Second Vaccination (Group 2 Compared to Group 1 and Group 3 (Combined)) | GMTs based on vaccinia-specific PRNT. Titers below the detection limit are included with a value of '1'. | Week 6 | 
| PRNT GMT 2 Weeks Following the Last Vaccination | GMTs based on vaccinia-specific PRNT. Titers below the detection limit are included with a value of '1'. | Week 6 (Groups 1 and 2), Week 14 (Group 3) | 
| PRNT GMT During Follow-up | GMTs based on vaccinia-specific PRNT. Titers below the detection limit are included with a value of '1'. Participants discontinued prior to the follow-up visits are excluded. | Weeks 30 and 56 (Groups 1 and 2), Weeks 38 and 64 (Group 3) | 
| Percentage of Participants With Seroconversion by ELISA | SC rate based on ELISA. SC 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. | within 64 weeks | 
| Percentage of Participants With Seroconversion by ELISA 2 Weeks Following the Second Vaccination (Group 2 Compared to Group 1 and Group 3 (Combined)) | SC rate based on ELISA. SC 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. | Week 6 | 
| Percentage of Participants With Seroconversion by ELISA 2 Weeks Following the Last Vaccination | SC rate based on ELISA. SC 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. | Week 6 (Groups 1 and 2), Week 14 (Group 3) | 
| Percentage of Participants With Seroconversion by ELISA During Follow-up | SC rate based on ELISA. SC 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. | Weeks 30 and 56 (Groups 1 and 2), Weeks 38 and 64 (Group 3) | 
| Percentage of Participants With Seroconversion by PRNT | SC rate based on PRNT. SC 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. | within 64 weeks | 
| Percentage of Participants With Seroconversion by PRNT 2 Weeks Following the Second Vaccination (Group 2 Compared to Group 1 and Group 3 (Combined)) | SC rate based on PRNT. SC 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. | Week 6 | 
| Percentage of Participants With Seroconversion by PRNT 2 Weeks Following the Last Vaccination | SC rate based on PRNT. SC 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. | Week 6 (Groups 1 and 2), Week 14 (Group 3) | 
| Percentage of Participants With Seroconversion by PRNT During Follow-up | SC rate based on PRNT. SC 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. | Weeks 30 and 56 (Groups 1 and 2), Weeks 38 and 64 (Group 3) |