The purpose of this study is to assess the safety of an experimental smallpox vaccine (MVA:
Modified Vaccinia Ankara) and to compare the body's immune (system that fights disease)
response to this vaccine. Participants will be assigned to 1 of 6 study groups. Each group
will include 12 subjects, 10 will receive the modified smallpox vaccine and two will receive
placebo, an inactive substance. The vaccine will be administered in 1 of 3 ways: under the
skin; in the muscle; or between the muscle and the skin. Groups A and B will receive Dryvax®
6-15 months after the initial MVA vaccine; groups C, D, E, and F will receive Dryvax® 6
months after the initial MVA vaccine. Study procedures will include documenting side effects
for 14 days after each vaccination, electrocardiogram (picture of the hearts activity) and
blood samples. Participants will be involved in study related procedures for up to 18
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 United States, 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/II trial to be conducted under a
placebo controlled double-blind, randomized allocation of study product. The purpose of this
study is to assess the safety and immunogenicity of ACAM 3000 MVA in healthy vaccinia-naïve
adult subjects. Participants will include 72 healthy, male or female, from the Boston
metropolitan area. Six dose regimens will be studied initially: 10^6 or 10^7 tissue culture
infectious dose 50 (TCID50) administered intradermally and 10^7 or 10^8 TCID50 administered
intramuscularly or subcutaneously as 2 immunizations 1 month apart. Each arm will be
comprised of 12 subjects, 10 of whom will receive ACAM3000 MVA and 2 of whom will receive
placebo. A subsequent vaccinia vaccination will be offered to all patients. Consenting
participants in Groups A and B will receive the vaccinia (Dryvax®) inoculation between 6 and
15 months after the initial MVA / placebo vaccination. Consenting participants in groups C,
D, E and F will receive the Dryvax® inoculation approximately 6 months after the initial MVA
/ placebo vaccination, coinciding with planned visit 13. Assessment of safety will be
carried out by observation and measurement of acute clinical and laboratory evidence of
reactions or toxicity; including clinical, electrocardiographic or laboratory evidence of
myopericarditis. Assessment of immunogenicity will be carried out by the measurement of
humoral and cell-mediated immune response to ACAM 3000 MVA and vaccinia, performed on blood
samples obtained at various times prior to and after immunization over the one year period
of the study. Response to vaccinia will be assessed clinically (effect on a "take") and the
results will be correlated with immune responses to MVA. Subjects will be followed for
reactogenicity. Clinical assessments and blood samples will be obtained sequentially for
- Age: greater than or equal to 18 and born after 1971.
- Complete a written assessment of understanding prior to enrollment and verbalize
understanding of all questions answered incorrectly.
- Informed consent: Be able, willing, and have signed the informed consent form.
- 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) A condition that is chronic or recurring and is life threatening b) A process that
would affect the immune response c) A process that would require medication that
affects the immune response d) A condition for which repeated injections or blood
draws may pose additional risk to the participant e) A condition that requires active
medical intervention or monitoring to avert grave danger to the participant's health
or well-being f) A condition or process in which signs or symptoms could be confused
with reactions to vaccine
- Willing to have blood samples stored for future smallpox related research.
- Hematology and chemistries within institutional normal limits for age and sex for the
following: hemoglobin, white blood cell (WBC)], serum creatinine, platelets,
troponin, alanine aminotransferase (ALT) [within 1.25 under normal limits (ULN),
aspartate aminotransferase (AST) (within 1.25 ULN), alkaline phos (within 1.25 ULN),
total bilirubin (within 1.25 ULN).
- Negative for Hepatitis B surface antigen and Hepatitis C virus (HCV) antibodies [If
HCV antibodies are positive, and negative for HCV by polymerase chain reaction (PCR),
subject is eligible]
- Negative FDA-approved human immunodeficiency virus (HIV) blood test within 8 weeks
prior to enrollment
- Normal urine dipstick or urinalysis:
1. Negative glucose, and
2. 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)
In addition to meeting ALL of the above criteria, FEMALE participants must meet BOTH of
the following criteria:
- Negative serum or urine beta-human chorionic gonadotropin (HCG) pregnancy test
performed within 24 hours prior to any vaccination.
- Reproductive status: A female participant either must:
1. not be of reproductive potential. Reproductive potential in women is defined as
not having reached menopause (no menses for one year) or having undergone
hysterectomy, bilateral oophorectomy, or tubal ligation.
2. be with a male partner(s) throughout the duration of the study who has undergone
successful vasectomy (A vasectomy is considered successful if a woman reports
that a male partner has (1) microscopic documentation of azospermia, or (2) a
vasectomy more than 2 years ago with no resultant pregnancy despite sexual
activity post-vasectomy.), or
3. 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:
i) condoms (male or female with or without a spermicide) ii) diaphragm or cervical
cap with spermicide iii) intrauterine device (IUD) iv) hormone-based therapy, e.g.,
contraceptive pills, Norplant, or Depo-Provera
In addition to the above criteria, female participants must meet the following criteria
prior to participating in Dryvax vaccination:
- Negative serum or urine beta-HCG pregnancy test performed within 24 hrs prior to
- Comply with one of the following methods of contraception for at least 21 days prior
to vaccination and at least 2 months post vaccination.
1. Hormonal contraception: such as implants, injectables, combined oral
2. Not be of reproductive potential: this may be due to
i) Hysterectomy or tubal ligation ii) The participant is in a monogamous relationship
with a male partner who has undergone successful vasectomy (Successful vasectomy as
defined as microscopic documentation of azospermia or a vasectomy more than two years
ago with no resultant pregnancy despite sexual activity post-vasectomy.) c) Sexual
- Prior vaccination with a vaccinia product. Determined by clinical evidence of
scarification or self-reported history of vaccinia vaccination (such as in the United
States military before 1991 or after 2003).
- 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.
- Currently using corticosteroid eye drops.
- Receipt of blood products within 120 days prior to initial study vaccine
- Receipt of immunoglobulin within 60 days prior to initial study vaccine
- Receipt of live attenuated vaccines within 30 days prior to initial study vaccine
- Receipt of investigational research agents within 30 days prior to initial study
- Receipt of medically indicated subunit or killed vaccines, e.g., influenza,
pneumococcal, or allergy treatment with antigen injections within 14 days prior to
initial study vaccine administration.
Participant has a history of any of the following:
- Acute febrile illness on the day of vaccination.
- Eczema or atopic dermatitis (past or present).
- Chronic exfoliative skin condition.
- Acute skin disorders of large magnitude (greater than 2x2 centimeters), e.g., burns
- History or presence of skin cancer at vaccination site.
- Heart disease including history of a myocardial infarction (MI), angina, congestive
heart failure (CHF), or pericardial pathology.
- 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).
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 greater than 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) less than 55 years of age or a female first-degree relative (mother or
sister) less than 65 years of age.
- Household contacts/sexual contacts with, or frequent and/or prolonged exposure to any
of the following:
a) Children less than 12 months of age b) Pregnant women or women who are breast
feeding c) Individuals with a history of eczema or atopic dermatitis d) Individuals
with chronic exfoliative skin disorders or skin disorders of large magnitude (greater
than 2x2 centimeters) e) Individuals with an immunosuppressive disorder such as HIV
infection, organ transplantation, or a condition requiring prolonged corticosteroid
- Electrocardiogram (ECG) with clinically significant findings, or features that would
interfere with the assessment of myo/pericarditis as determined by the consulting
cardiologist, including any of the following: (1) Conduction disturbance (complete
left or incomplete right bundle branch block or nonspecific intraventricular
conduction disturbance with waves of ventricular activity of the heart traced on an
ECG (QRS) greater than 120 millisecond (ms), atrioventricular (AV) block of any
degree, or QTc prolongation (greater than 440 ms); (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.
- Known or suspected allergy to any component of the vaccine or diluent.
- Allergy to eggs or blood products [including immunoglobulin (IgG) or vaccinia
- Serious adverse 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
- Autoimmune disease.
- Asthma that is unstable, e.g., use of oral or intravenous corticosteroids,
hospitalization or intubation during the past 2 years a) Inhaled steroids are not
- Diabetes mellitus type I or type II including cases controlled with diet alone. Not
excluded: A participant with past gestational diabetes is not excluded.
- 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 intramuscular (IM) injections and blood draws without any adverse
experience, is not excluded.
- Seizure disorder not excluded: A participant with a remote history (over 3 years
ago) of seizure who has not required medications 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.
- Asplenia. Any condition resulting in the absence or removal of the spleen.
- Psychiatric condition that precludes compliance with the protocol. Specifically
excluded are persons with one or more of the following:
a) Psychoses within the past 5 years. b) 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.
- Any medical, psychiatric, or social condition, or occupational or other
responsibility that, in the judgment of the investigator, would interfere with, or
serve as a contraindication to, protocol adherence or a participant's ability to give
- Female participants: Participant is pregnant and/or breast-feeding.
In addition to the above criteria, the following exclusion criteria apply to those
participants consenting to Dryvax vaccination:
-A history of the following:
1. Excessive scarring
2. Known or suspected allergy to any component of the vaccine or diluent including
polymyxin B sulfate, dihydrostreptomycin sulfate, chlorotetracycline hydrochloride,
neomycin, and phenol.
3. Known allergy to cidofovir or probenecid -Abnormal renal function:
a) A calculated creatinine clearance less than 80 mL/min based on the following formulas:
i) Males: [(140 - age in years) X weight in kilograms (kg)]/(72 X serum creatinine) ii)
Females: 0.85 X [(140 - age in years) X weight in kg]/(72 X serum creatinine)