This study compares the capacity to produce adverse reactions and the capability to produce an immune response of 6 dose regimens (arms) of a modified smallpox vaccine. Each arm will include 12 subjects, 10 of whom will receive the modified smallpox vaccine and two will receive an inactive substance or preparation used as a standard of comparison for checking or verifying the results of the vaccine. Both participants and investigators are unaware of the intervention assignment. Participants are assigned to interventional groups by chance. Subjects will be followed for the capacity of the vaccine to produce adverse reactions and blood samples will be obtained to see if the vaccine produced an immune response.

Condition	Intervention	Phase
Variola major (smallpox)	Vaccine: ACAM3000 MVA  Vaccine: GMP Grade PBS	Phase I Phase II

Further Study Details: 

Expected Total Enrollment:  72

The emergence of smallpox as a potential agent of bioterrorism has heightened concern about the vulnerability of the population to infection with this agent, and has led to proposals to undertake large scale smallpox immunization of military personnel and "first responders" in the U.S., including certain health care workers. A particularly promising vaccine approach to the development of an effective, yet less reactogenic vaccine to smallpox is the use of Modified Vaccinia Ankara (MVA) as a vaccine. Despite the established efficacy of smallpox vaccination, the parameters of protective immunity against smallpox infection are incompletely understood. This is a phase I trial to be conducted under a placebo controlled, double-blind, randomized allocation of smallpox vaccine. The purpose of this study is to assess the safety and immunogenicity of ACAM 3000 MVA in healthy vaccinia-naïve adult subjects. Six dose regimens will be studied initially: 10E6 or 10E7 TCID50, administered ID, and 10E7 and 10E8 TCID50 administered ID or SC as two immunizations one month apart. Assessment of safety will be carried out by observation and measurement of acute clinical and laboratory evidence of toxicity; including clinical, electrocardiographic or laboratory evidence of myopericarditis. Subjects will be followed for one year. Assessment of immunogenicity will be carried out by the measurement of humoral and cell-mediated immune response to ACAM 3000 MVA, performed on blood samples obtained at various times prior to and after immunization over the one year period of the study. Blinding will be maintained to active vaccine or placebo within each dose and route (IM, SC, or ID) of administration.

Ages Eligible for Study:  18 Years   -   33 Years,  Genders Eligible for Study:  Both

Accepts Healthy Volunteers

Criteria

Inclusion Criteria:

1. Age: greater than or equal to 18 years of age and born after 1971.
2. Complete a written assessment of understanding prior to enrollment; verbalize understanding of all questions answered incorrectly.
3. Informed Consent: be able, willing and have signed the informed consent form.

4. Health: be in good general health without clinically significant medical history, physical examination findings, or clinically significant abnormal laboratory results. A clinically significant condition or process includes one or more of the following:

   - A condition that is chronic and reoccurring or life threatening

   - A process that would affect the immune response

   - A process that would require medication that affects the immune response

   - A condition for which repeated injections or blood draws may pose additional risk to the participant

   - A condition that requires active medical intervention or monitoring to avert grave danger to the participant''''s health or well-being

   - A condition or process in which signs or symptoms could be confused with reactions to vaccine

5. Willing to have blood samples stored for future smallpox related research
6. Hematology and chemistries within institutional normal limits for age and sex for the following: Hematocrit, WBC, serum creatinine, ALT, platelets, troponin
7. Negative for Hepatitis B surface antigen and Hepatitis C virus antibodies (if HCV antibodies are positive, and negative for HCV by PCR, subject is eligible)
8. Negative FDA-approved HIV blood test within 8 weeks prior to enrollment

9. Normal urine dipstick or urinalysis:

   - Negative glucose and

   - Negative or trace protein, and negative or trace hemoglobin (if trace hemoglobin is present, a urinalysis is required to exclude participants with counts greater than the institutional normal range)

10. Females must meet all criteria above plus both of the following:

    1. Negative serum or urine ß-HCG pregnancy test performed within 24 hours prior to any vaccination

    2. Reproductive status: A female participant either must:

       - not be of reproductive potential

       - be with a male partner(s) throughout the duration of the study who has undergone successful vasectomy, or

       • agree to avoid pregnancy through alternative methods and agree to consistently use contraception for at least 21 days prior to enrollment until the last protocol visit. Contraception is defined as using one of the following methods:
    1. condoms (male or female with or without spermicide)
    2. diaphragm or cervical cap with spermicide
    3. intrauterine device (IUD)
    4. hormone-based therapy, e.g., contraceptive pills, Norplant, or Depo-Provera

Exclusion Criteria:

1. Prior vaccination with a vaccinia product. Determined by clinical evidence of scarification or self-reported history of vaccinia vaccination (such as the US military before 1991 or after 2003).
2. Immunosuppressive medications within 168 days prior to initial study vaccine administration, e.g. oral/parenteral corticosteroids, and/or cytotoxic medications. Not excluded: A participant using any of the following is not excluded: corticosteroid nasal spray for allergic rhinitis; or topical corticosteroids as prescribed by a physician for an acute, uncomplicated dermatitis; or over the counter medications (including topical corticosteroids for an acute, uncomplicated dermatitis); use of rapidly tapered steroids for an acute isolated condition, which does not include asthma within 28 days prior to vaccine administration.
3. Currently using corticosteroid eye drops.
4. Receipt of blood products within 120 days prior to initial study vaccine administration.
5. Receipt of immunoglobin within 60 days prior to initial vaccine administration.
6. Receipt of live attenuated vaccines within 30 days prior to initial vaccine administration.
7. Receipt of investigational research agents within 30 days prior to initial vaccine administration.
8. Receipt of medically indicated subunit or killed vaccines, e.g., influenza, pneumococcal, or allergy treatment with antigen injections within 14 days prior to initial vaccine administration.

Participant has a history of any of the following:

9. Acute febrile illness on the day of vaccination. 10. Eczema or atopic dermatitis (past or present). 11. Chronic exfoliate skin condition 12. Acute skin disorders of large magnitude (greater than 2x2cm), e.g., burns or lacerations 13. History or presence of skin cancer at vaccination site. 14. Heart disease including history of an MI, angina, CHF, or pericardial pathology.

15. 10% 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: This criterion applies only to subjects 20 years of age and older AND only if at least one of the following applies:

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.

16. Household contacts/sexual contacts with, or frequent and/or prolonged exposure to any of the following:

1. Children <12 months of age
2. Pregnant women or women who are breast feeding
3. Individuals with a history of eczema or atopic dermatitis
4. Individuals with chronic exfoliative skin disorders or skin disorders of large magnitude (greater than 2x2 cm)

5. Individuals with an immunosuppressive disorder such as HIV infection, organ transplantation, or a condition requiring prolonged corticosteroid therapy 17. ECG with clinically significant findings, or features that would interfere with the assessment of myo/pericarditis, including any of the following: (1) conduction disturbance (complete left or incomplete right bundle branch block or nonspecific intraventricular conduction disturbance with QRS >120 ms, AV block of any degree, or QTc prolongation (>440ms)); (2) Repolarization (ST segment or T wave) abnormality; (3) Significant atrial or ventricular arrhythmia; (4) Frequent atrial or ventricular ectopy (e.g. frequent premature atrial contractions, 2 premature ventricular contractions in a row); (5) ST elevation consistent with ischemia; (6) Evidence of past or evolving myocardial infarction.

   18. Known or suspected allergy to any component of the vaccine or diluent. 19. Allergy to eggs or blood products (including IgG) or neomycin. 20. Serious adver se reactions to vaccines including anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. Not excluded: A participant who had an adverse reaction to pertussis vaccine as a child is not excluded.

   21. Autoimmune disease 22. Immunodeficiency 23. Asthma that is unstable, e.g., use of oral or intravenous corticosteroids, hospitalization or intubation during the past 2 years

   • Inhaled steroids are not permissible 24. Diabetes mellitus type I or II including cases controlled with diet alone. Not excluded: A participant with past gestational diabetes is not excluded.

     25. Bleeding disorder diagnosed by a doctor, e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions. Not excluded: A participant who states he/she has easy bruising or bleeding, but does not carry a formal diagnosis and has had IM injections and blood draws without any adverse experience, is not excluded.

     26. Seizure disorder. Not excluded: A participant with a remote history (over 3 years ago) of seizure who has not required medication for over 3 years is not excluded if (a) the seizures were febrile seizures under the age of 2, or (b) secondary to alcohol withdrawal, or (c) if the seizure only occurred once.

     27. Asplenia. Any condition resulting in the absence or removal of the spleen. 28. Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with one or more of the following:

   • Psychoses within the past 5 years.

   • Suicidal ideation occurring within 2 years prior to enrollment. Not excluded: A participant with a remote history (greater than 3 years) of a suicide attempt or suicide gesture is not excluded if the investigator finds the participant (a) to be of sound mental health; and (b) the suicide attempt was a well-defined, isolated event; and (c) the cause or inciting factor(s) no longer has relevance to the individual. A participant currently in therapy, due to a suicide attempt or gesture, or suicidal ideation, may be enrolled only when the participant''''s current therapist or health care provider provides documentation that the participant currently is not suicidal.

     29. Any medical, psychiatric or social condition, or occupational or other responsibility that, in the judgment of the investigator, would interfere with, or serve as contraindication to, protocol adherence or a participant''''s ability to give informed consent.

     30. Female participants: Participant is pregnant and/or breast-feeding.

Please refer to this study by ClinicalTrials.gov identifier  NCT00133575

Lindsey Baden      (617) 732-6801    lbaden@partners.org

Massachusetts
      Harvard Medical School, Boston,  Massachusetts,  02115,  United States
      Beth Israel Deaconess Medical Center, Boston,  Massachusetts,  02215,  United States
      Dana Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States
      Brigham and Women''''s Hospital, Boston,  Massachusetts,  02115,  United States

Study ID Numbers:  05-0010
Last Updated:  August 22, 2005
Record first received:  August 19, 2005
ClinicalTrials.gov Identifier:  NCT00133575
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-08-23