Vaccine Therapy in Healthy Volunteers With or Without Previous Exposure to Cytomegalovirus

Study Overview
=================
Brief Summary
-----------------
This phase I trial studies the side effects and the best dose of vaccine therapy in healthy volunteers with or without previous exposure to cytomegalovirus. Vaccines made from a gene-modified virus may help the body build an immune response and may help prevent cytomegalovirus infection.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To establish a biological optimal dose of the cytomegalovirus (CMV)-modified vaccinia Ankara (MVA) Triplex vaccine (multi-CMV epitope modified vaccinia Ankara vaccine). II. To determine if the vaccine is safe and well tolerated in healthy volunteers at these doses. SECONDARY OBJECTIVES: I. To provide preliminary evidence of CMV-MVA Triplex vaccine driven expansion of CMV-specific immune responses that would support further evaluation of this vaccine in hematopoietic cell transplantation (HCT) recipients. II. To confer CMV-specific immunity to CMV-negative volunteers and to determine the duration of immune enhancement of CMV-specific cell mediated immunity (CMI) function up to 12 months following immunization of healthy volunteers. OUTLINE: This is a dose-escalation study. Participants receive multi-CMV epitope modified vaccinia Ankara vaccine intramuscularly (IM) followed by a booster injection 28 days later in the absence of unacceptable toxicity. After completion of study treatment, participants are followed up for 12 months.

Official Title
-----------------
Phase I Evaluation of a CMV-MVA Triplex Vaccine: Safety and Biologically Effective Dose in Healthy Volunteers With or Without Prior Immunity to CMV and Vaccinia

Conditions
-----------------
Cytomegalovirus Infection, Healthy, no Evidence of Disease

Intervention / Treatment
-----------------
* Biological: multi-CMV epitope modified vaccinia Ankara vaccine
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Sodium range from within normal institutional limits to less than a grade I toxicity Potassium range from within normal institutional limits to less than a grade I toxicity Chloride range from within normal institutional limits to less than a grade I toxicity Carbon dioxide range from within normal institutional limits to less than a grade I toxicity Glucose range from within normal institutional limits to less than a grade I toxicity Alkaline phosphatase (AP) range from within normal institutional limits to less than a grade I toxicity Aspartate aminotransferase (AST), alanine aminotransferase (ALT) range from within normal institutional limits to less than a grade I toxicity Blood urea nitrogen (BUN) range from within normal institutional limits to less than a grade I toxicity Creatinine range from within normal institutional limits to less than a grade I toxicity Lactic dehydrogenase (LDH) range from within normal institutional limits to less than a grade I toxicity Total bilirubin range from within normal institutional limits to less than a grade I toxicity Uric acid range from within normal institutional limits to less than a grade I toxicity Albumin > lower limit of normal institutional limits White blood count range from within normal institutional limits to less than a grade I toxicity Hemoglobin (HGB) range from within normal institutional limits to less than a grade I toxicity Hematocrit (HCT) range from within normal institutional limits to less than a grade I toxicity Platelet count is within the lower limit of normal institutional limits and not more than 1.5 times the upper limit of normal institutional limits Hepatitis B virus (HBV) surface antigen negative and hepatitis C virus (HCV) seronegative; human immunodeficiency virus (HIV)-1 seronegative Currently not taking daily medications for chronic or intercurrent illness; those medications which are excepted from this rule are thyroid replacement, estrogen replacement, dietary vitamins and protein supplements, and any medications not known or likely to be immunosuppressive, as determined by the principal investigator (PI) No surgery in past 6 months which required general anesthesia, but minor procedures, such as dental surgery and superficial diagnostic biopsies, are permitted No diagnosis which has been associated with immunodeficiency No active infection for which the subject is receiving treatment Framingham Risk Score for cardiovascular disease =< 10%; no history of heart disease, e.g. previous treated arrhythmia or myocardial infarction; no horizontal positioning-induced or activities of normal living exercise-induced shortness of breath; no history of stroke or claudication; no current treatment with medication for high cholesterol or other lipid abnormality; a documented electrocardiogram (ECG) and cardiac troponin must be within normal institutional limits in the past 30 days; normal ECG with sinus tachycardia or  normal ECG with sinus bradycardia is allowable based on a history of absent cardiac/exercise related symptoms as determined by the P.I. in consultation with a senior staff cardiologist No history of or prior treatment for diabetes type 1 or diabetes type 2 Women of childbearing age must have a negative urine pregnancy test and must not be planning to become pregnant within the next 6 months No history of adverse events with a prior smallpox vaccination SECONDARY ELIGIBILITY CRITERIA: It is anticipated that there could be a delay of 1-3 months between screening and actual vaccination; alternatively, there could be a delay due to availability of the vaccine; therefore, prior to registration for vaccination, the following secondary eligibility criteria must be met: If not tested in past 4 months, serum chemistries and blood counts are within normal limits; hepatitis B virus (HBV) surface antigen negative and hepatitis C virus (HCV) seronegative; HIV-1 antibody negative Women of childbearing age must have a urine pregnancy test performed within 48 hours of each vaccine administration with a negative result Laboratory values prior to booster injection may include grade 1 laboratory abnormalities, but any grade >= grade 2 will exclude the subject from a booster injection Exclusion Criteria: Any previous condition, or one that becomes known during the screening period, that would suggest that the individual could be immunologically impaired, or for which this study would pose a danger to him/herself or about which the P.I., in evaluating the subject for eligibility, determines that this exclusion is appropriate Subjects are excluded who have a history of cancer other than basal cell skin cancer, or any condition, psychiatric or otherwise, that would preclude informed consent, consistent follow-up or compliance with any aspect of the study (e.g., untreated schizophrenia or other significant cognitive impairment, etc. as determined by the PI. In addition, allergic diatheses as define by a history of asthma, anaphylaxis, or generalized urticaria, or by daily use of antihistamines, episodic (more than once in past 3 months) inhalational medications including steroidal agents, non-steroidal agents, or cromolyn sodium Subjects with severe migraine headaches (more than one per month on average in the past 6 months or requiring preventive medications) are excluded Any of the following cardiac findings of ECG abnormality: Conduction disturbance (complete left or right bundle branch block, intraventricular conduction disturbance with QRS > 120 ms, atrioventricular block [AV] block of any degree, and corrected QT [QTc] prolongation > 450 msec for men and > 460 msec for women) Repolarization (ST segment or T wave) abnormality Significant atrial or ventricular arrhythmia, including frequent ectopy (e.g., 2 premature ventricular contractions in a row; and Evidence of past myocardial infarction Any previous condition, or one that becomes known during the screening period, that would suggest that the technicians and health professionals involved in the study would be exposed to specific infectious risk Treatment with whole or subunit CMV or poxvirus vaccine in the last 12 months Men with partners of child-bearing potential and women of child-bearing potential who are not willing to use medically effective birth control methods, e.g. contraceptive pill, condom, or diaphragm, and continue this for 6 weeks after the second and last dose of vaccine Subjects who have had a live vaccine =< 30 days prior to administration of study vaccine or subjects who are =< 2 weeks within administration of inactivated vaccines (e.g. influenza vaccine) Persons who are employed by or are a student at City of Hope and are in a chain of command that reports directly to persons listed on the protocol as Principal Investigator or Co-Investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (CMV-MVA Triplex vaccine)<br>Participants receive multi-CMV epitope modified vaccinia Ankara vaccine IM followed by a booster injection 28 days later in the absence of unacceptable toxicity. | Biological: multi-CMV epitope modified vaccinia Ankara vaccine<br>* Given IM<br>* Other names: CMV-MVA triplex vaccine;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Successful completion of 2 injections without dose-limiting toxicity (DLT) according to the Division of Microbiology and Infectious Diseases (DMID) adult toxicity tables |  | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evidence of CMV-MVA Triplex vaccine driven expansion of CMV-specific immune responses to support further evaluation of this vaccine in HCT recipients. | Expansion of CMV-specific T-cells in peripheral blood mononuclear cell (PBMC)will be evaluated by flow cytometry, immunocytochemistry (ICC) assays, and enzyme-linked immunosorbent spot (ELISPOT) | Up to 1 year | 
| Frequency of polyfunctional cluster of differentiation (CD)4+ and CD8+ T cells recognizing CMV Ag, expressed as concentrations | A one-sample signed-rank test will be used to compare pre- and post-vaccination CD4+ and CD8+ T cell levels. A secondary analysis will model cell concentrations as a function of time, dose, and CMV serostatus. Mixed models and generalized estimating equations will be used to permit quantitative estimation and flexible investigation of potentially interacting covariables. | Up to 1 year |