combination study with mva bn and dryvax

Conditions: Smallpox

Summary: the overall goals of this study are to expand the available data on the safety and immunogenicity of mva-bn in vaccinia-naive adults and to determine the optimum dose of mva-bn to induce immune responses and attenuate dryvax take reactions. participants will include 90 healthy volunteers, ages 18-32 years. participants will be randomly assigned to 1 of 6 study groups (groups a-f). participants will be involved in study related procedures for up to 2 years. during this time, volunteers will return periodically for blood draws to check immune responses.

the primary goal of this phase i trial is to expand the available data on the safety and immunogenicity of mva-bn in vaccinia-naïve adults. the secondary goals of this vaccine trial are: to determine the optimum dose of mva-bn, given twice, to induce an immune response and attenuate dryvax® take reactions; and to compare the ability of 2 routes of administration of mva-bn, subcutaneous and intramuscular, to induce an immune response at the highest tested dose. a total of 90 healthy adult volunteers ages 18-32 will participate in this study. the volunteers will be randomly assigned to 1 of 6 groups to be immunized with: mva-bn (subcutaneously) at 1 of 3 dose levels and dryvax® (per scarification); placebo (subcutaneously) and dryvax® (per scarification); mva-bn (subcutaneously) at the highest dose level and placebo scarification; or mva-bn (intramuscularly) at the highest dose level and dryvax® (per scarification). the study will last about 30 months. each volunteer's participation will last 6 months for all treatment groups. subjects randomized to treatment groups d and e will have follow-up for 2 years. during this time, volunteers will return periodically for blood draws to check immune responses. subjects will require visits for dressing changes as needed post-dryvax vaccination. variables to be investigated include: adverse events and side effects to the vaccines, and immunogenicity testing including antibody and cellular responses to the vaccines.

Eligibility criteria:
inclusion criteria: * ages 18-32. * never received smallpox vaccination. * read, signed and dated informed consent document. * availability for follow-up for the planned duration of the study two years after first immunization. * acceptable medical history by screening evaluation and limited physical examination. * for women, negative serum pregnancy test at screening and negative urine or serum pregnancy test within 24 hours prior to vaccination. * if the volunteer is female and of child bearing potential, she agrees to use acceptable contraception, and not become pregnant for at least 56 days after the last vaccination. a woman is considered of child bearing potential unless post-menopausal or surgically sterilized. \[acceptable contraception methods are restricted to effective intrauterine devices (iuds) or licensed hormonal products with use of method for a minimum of 30 days prior to vaccination.\] women who are not sexually active must agree to use one of the acceptable contraception methods if they are of childbearing potential. * negative elisa for hiv. * alt\<1.25 times institutional upper limit of normal. * negative hepatitis b surface antigen and negative antibody to hepatitis c virus. * negative urine glucose by dipstick or urinalysis. * adequate renal function defined as a serum creatinine less than or equal to 1.4mg/dl for males and less than or equal to 1.2mg/dl for females; urine protein \< 30 mg/dl or none or trace proteinuria (by urinalysis or dipstick); and a calculated creatine clearance greater than or equal to 80 ml/min. based on the following formulas: * males \[(140-age in years) x weight in kg\]/(72 x serum creatinine) * females 0.85x\[(140-age in years) x weight in kg\]/(72 x serum creatinine) * ecg without clinical significance (e.g., all kinds 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, or 2 premature ventricular contractions (pvc) in a row, or st elevation consistent with ischemia) * cbc: hemoglobin \>11g/dl; white blood cells greater than 2,500 and less than 11,000/cubic mm; platelets greater than or equal to 140,000/cubic mm. exclusion criteria: * history of immunodeficiency. * typical vaccinia scar. * known or suspected history of smallpox vaccination. * military service prior to 1989 or after january 2003. * known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease; diabetes mellitus; moderate to severe kidney impairment. * malignancy, including squamous cell skin cancer or basal cell skin cancer at vaccination site or history of skin cancer at the vaccination site. * active autoimmune disease. persons with vitiligo or thyroid disease on thyroid replacement are not excluded. * history of keloid formation. * history of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, or other heart condition under the care of a doctor. * 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 for estimating your 10-year risk of having a heart attack, located at the following url: http://hin.nhlbi.nih.gov/atpiii/calculator.asp. note: this criterion applies only to volunteers 20 years of age and older. * abnormal troponin i. * use of immunosuppressive medication. corticosteroid nasal sprays are permissible. persons who have used topical steroid can be enrolled after their therapy is completed. * medical or psychiatric condition or occupational responsibilities that preclude volunteer compliance with the protocol. * any history of "illegal" injection drug use. * receipt of inactivated vaccine 14 days prior to vaccination. * receipt of live attenuated vaccines within 30 days of vaccination. * use of experimental agents within 30 days prior to vaccination. * receipt of blood products or immunoglobulin in the 6 months prior to vaccination. * acute febrile illness (greater than or equal to 100.5 degrees f) on the day of vaccination. * pregnant or lactating women. * eczema of any degree or history of eczema. * people with atopic dermatitis, varicella zoster, chronic exfoliative skin disorders/conditions or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2x2 cm. * household contacts/sexual contacts with, or occupational exposure to (other than minimal contact), any of the following: pregnant women; children \<12 months of age; people with or history of eczema; people with atopic dermatitis, varicella zoster, chronic exfoliative skin disorders/conditions or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2x2 cm; people with immunodeficiency disease or use of immunosuppressive medications. * any condition that, in the opinion of the investigator, might interfere with study objectives. * known allergies to or any component of mva or mva-bn vaccine (e.g., tris(hydroxymethl)-amino methane, sodium chloride, sucrose, dextran, l-glutamic acid monopotassium, chicken embryo fibroblast proteins, gentamycin). * known allergy to egg or aminoglycoside. * known allergies to any component of the dryvax® vaccine (e.g. polymyxin b sulfate, dihydrostreptomycin sulfate, chlorotetracycline hydrochloride, neomycin sulfate). * known allergies to any known component of the dryvax® diluent (i.e. glycerin and phenol). * known allergies to any known components of vaccinia immunoglobulin (vig), i.e. thimerosal or previous allergic reaction to immunoglobulins. * known allergies to cidofovir or probenecid. * study personnel.

Keywords: smallpox, vaccine