Evaluating the Safety and Immune Response of a Prime-Boost HIV Vaccine Regimen in Healthy, HIV-Uninfected, Vaccinia-Naive Adults

Although multiple candidate HIV vaccines are being studied, there is not yet an effective
preventive HIV vaccine. This study will test the safety and immune responses of prime-boost
regimens of two HIV vaccines: two injections of GEO-D03 DNA priming vaccine followed by
either two or three boosting injections of MVA/HIV62B (MVA62B) vaccine.

This study will enroll 48 healthy, HIV-1-uninfected, vaccinia-naive adults into 1 of 3
groups. Participants within each group will be randomly assigned to receive either the study
vaccine regimen (40 total participants) or placebo vaccine regimen (8 total participants).

The total study duration will be approximately 45 months. Participants in Group 1 will
attend clinic visits for 14 months followed by annual health contacts, for a total of 3
years after initial study injection. Participants in Group 2 will attend clinic visits for
22 months followed by annual health contacts, for a total of 3 years after initial study
injection. Participants in Group 3 will attend clinic visits for 20 months followed by
annual health contacts, for a total of 3 years after initial study injection. Participants
in Group 1 will have 17 study visits, participants in Group 2 will have 23 visits, and
participants in Group 3 will have 21 visits.

At the screening visit, participants will give a medical history and undergo a complete
physical exam, electrocardiogram (ECG), urine collection, blood collection, interview, HIV
test, and pregnancy test (for participants who were born female). Participants will receive
an intramuscular (IM) vaccination (study vaccine or placebo) into the deltoid on the
schedule assigned to their group. The vaccination schedule is as follows: Group 1
participants will receive an injection on Days 0, 56, 112, 168, and 224; Group 2
participants will receive an injection on Days 0, 56, 112, 168, and 303; Group 3
participants will receive an injection on Days 0, 56, 112, and 224. On vaccination visits,
participants will also undergo an abbreviated physical exam, a pregnancy test (for
participants who were born female), risk-reduction counseling, and blood collection.
Immediately following vaccination, participants will remain in the clinic for observation
for 30 minutes; participants will be given a post-vaccination symptom log and instructed on
how to complete it. Follow-up visits will consist of a brief physical exam, blood
collection, and interview; some follow-up visits may also consist of a urine collection, HIV
test, or ECG.

The last clinic visit will be at Day 425 for participants in Group 1, Day 667 for
participants in Group 2, and Day 607 for participants in Group 3; after this visit,
participants will be contacted for annual health follow-up consisting of confirming vital
status, collecting safety information, and reporting a new HIV diagnosis or a pregnancy. A
clinic visit will only be required if HIV confirmatory testing is necessary.

Inclusion Criteria:

- Access to a participating HIV Vaccine Trials Network (HVTN) clinical research site
(CRS) and willingness to be followed for the planned duration of the study

- Ability and willingness to provide informed consent

- Assessment of understanding: participant demonstrates understanding of this study and
completes a questionnaire prior to first vaccination with verbal demonstration of
understanding of all questionnaire items answered incorrectly

- Willingness to receive HIV test results

- Willingness to discuss HIV infection risks, amenable to HIV risk-reduction
counseling, and committed to maintaining behavior consistent with low risk of HIV
exposure through the last required protocol clinic visit

- Willing to be contacted annually after completion of scheduled clinic visits for a
total of 3 years following initial study injection

- Agrees not to enroll in another study of an investigational research agent prior to
completion of last required protocol clinic visit (excludes annual contacts for
safety surveillance)

- Good general health as shown by medical history, physical exam, and screening
laboratory tests

- Assessed by the clinic staff as being at low risk of HIV infection

- Hemoglobin greater than or equal to 11.0 g/dL for participants who were born female,
or greater than or equal to 13.0 g/dL for participants who were born male

- White blood cell (WBC) count of 3,300 to 12,000 cells/mm^3

- Total lymphocyte count greater than or equal to 800 cells/mm^3

- Remaining differential either within institutional normal range or with site
physician approval

- Platelet level of 125,000 to 550,000/mm^3

- Chemistry panel: ALT, AST, alkaline phosphatase, and creatinine values less than or
equal to institutional upper limits of normal

- Negative HIV-1 and HIV-2 blood test: U.S. participants must have a negative Food and
Drug Administration (FDA)-approved immunoassay

- Negative hepatitis B surface antigen (HBsAg)

- Negative anti-hepatitis C virus (HCV) antibodies or negative HCV polymerase chain
reaction (PCR) if the anti-HCV is positive

- Normal urine: negative urine glucose, negative or trace urine protein, and negative
or trace urine hemoglobin (if trace hemoglobin is present on dipstick, a microscopic
urinalysis for red blood cells [RBCs] within institutional normal range)

- Participants who were born female: negative serum or urine beta human chorionic
gonadotropin (HCG) pregnancy test performed prior to vaccination on the day of
initial vaccination

- Reproductive status: A participant who was born female must either: (1) Agree to
consistently use effective contraception for sexual activity that could lead to
pregnancy, from at least 21 days prior to enrollment through the last required
protocol clinic visit. Effective contraception is defined as using any of the
following methods: condoms (male or female) with or without a spermicide, diaphragm
or cervical cap with spermicide, intrauterine device (IUD), hormonal contraception,
or successful vasectomy in the male partner (considered successful if a participant
reports that a male partner has either documentation of azoospermia by microscopy or
a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity
postvasectomy); or (2) Not be of reproductive potential, such as having reached
menopause (no menses for 1 year) or having undergone hysterectomy, bilateral
oophorectomy, or tubal ligation; or (3) Be sexually abstinent.

- Participants who were born female must also agree not to seek pregnancy through
alternative methods, such as artificial insemination or in vitro fertilization until
after the last required protocol clinic visit

Exclusion Criteria:

- Vaccinia (smallpox) vaccine determined by (1) clinical evidence of vaccinia
scarification; (2) self-reported history of vaccinia vaccination; (3) date of birth;
or (4) U.S. military service prior to 1989 or after December 2002 (not excluded: a
participant born before 1975, or with past U.S. military service, who self-reports
he/she did not receive vaccinia vaccine and has no evidence of scarification)

- Untreated or incompletely treated syphilis infection

- HIV vaccine(s) received in a prior HIV vaccine trial. For potential participants who
have received control/placebo in an HIV vaccine trial, the HVTN 094 Protocol Safety
Review Team (PSRT) will determine eligibility on a case-by-case basis.

- Non-HIV experimental vaccine(s) received within the last 5 years in a prior vaccine
trial. Exceptions may be made for vaccines that have subsequently undergone licensure
by the FDA. For potential participants who have received control/placebo in an
experimental vaccine trial, the HVTN 094 PSRT will determine eligibility on a
case-by-case basis. For potential participants who have received an experimental
vaccine(s) greater than 5 years ago, eligibility for enrollment will be determined by
the HVTN 094 PSRT on a case-by-case basis.

- Immunosuppressive medications received within 168 days before first vaccination. Not
excluded: (1) corticosteroid nasal spray for allergic rhinitis; (2) topical
corticosteroids for mild, uncomplicated dermatitis; or (3) oral/parenteral
corticosteroids given for non-chronic conditions not expected to recur (length of
therapy 10 days or less with completion at least 30 days prior to enrollment)

- Blood products received within 120 days before first vaccination

- Immunoglobulin received within 60 days before first vaccination

- Live attenuated vaccines other than influenza vaccine received within 30 days before
first vaccination or scheduled within 14 days after injection (e.g., measles, mumps,
and rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever)

- Investigational research agents received within 30 days before first vaccination

- Intent to participate in another study of an investigational research agent during
the planned duration of the HVTN 094 study

- Influenza vaccine or any vaccines that are not live attenuated vaccines and were
received within 14 days prior to first vaccination (e.g., tetanus, pneumococcal,
hepatitis A or B)

- Allergy treatment with antigen injections within 30 days before first vaccination or
that are scheduled within 14 days after first vaccination

- Current anti-tuberculosis (TB) prophylaxis or therapy

- Clinically significant medical condition, physical examination findings, clinically
significant abnormal laboratory results, or past medical history with clinically
significant implications for current health. A clinically significant condition or
process includes but is not limited to:

- A process that would affect the immune response

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

- Any contraindication to repeated injections or blood draws

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

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

- Any condition specifically listed among the exclusion criteria below

- Any medical, psychiatric, occupational, or other condition that, in the judgment of
the investigator, would interfere with or serve as a contraindication to protocol
adherence, assessment of safety or reactogenicity, or a participant's ability to give
informed consent

- 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 a nonanaphylactic adverse reaction to pertussis vaccine as a
child)

- Hypersensitivity to eggs or egg products

- History of myocarditis, pericarditis, cardiomyopathy, congestive heart failure with
permanent sequelae, clinically significant arrhythmia (including any arrhythmia
requiring medication, treatment, or clinical follow-up)

- ECG with clinically significant findings or features that would interfere with the
assessment of myocarditis/pericarditis as determined by a contract ECG lab or
cardiologist, including any of the following:

- Conduction disturbance (complete left or complete right bundle branch block or
nonspecific intraventricular conduction disturbance with QRS greater than or
equal to 120 ms, PR interval greater than or equal to 220 ms, any second or
third degree atrioventricular (AV) block, or QTc prolongation greater than 450
ms)

- Repolarization (ST segment or T wave) abnormality that will interfere with the
assessment of myocarditis/pericarditis

- Significant atrial or ventricular arrhythmia

- Frequent atrial or ventricular ectopy (e.g., frequent premature atrial
contractions or two premature ventricular contractions in a row)

- ST elevation consistent with ischemia; or

- Evidence of past or evolving myocardial infarction

- Autoimmune disease

- Immunodeficiency

- Asthma other than mild, well-controlled asthma. Exclude a participant who:

- Generally uses a bronchodilator (beta2 agonist) daily

- In the past year, has any of the following:

- More than one exacerbation of symptoms treated with oral steroids (note:
oral/parenteral steroid use for asthma is exclusionary within 168 days
before first vaccination)

- Routinely used moderate to high dose inhaled corticosteroids (e.g., more
than the equivalent of 250 mcg fluticasone, 400 mcg budesonide, 500 mcg
beclomethasone, or 1,000 mcg triamcinolone/flunisolide, as a daily dose) or
theophylline for asthma; or

- Needed emergency care, urgent care, hospitalization, or intubation for
asthma

- Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. (not
excluded: history of isolated gestational diabetes)

- Thyroidectomy or thyroid disease requiring medication during the last 12 months

- History of hereditary angioedema, acquired angioedema, or idiopathic angioedema

- Hypertension:

- If a person has been found to have elevated blood pressure or hypertension
during screening or previously, exclude for blood pressure that is not well
controlled. Well-controlled blood pressure is defined as consistently less than
or equal to 140 mm mercury (Hg) systolic and less than or equal to 90 mm Hg
diastolic, with or without medication, with only isolated, brief instances of
higher readings that must be less than or equal to 150 mm Hg systolic and less
than or equal to 100 mm Hg diastolic. For these participants, blood pressure
must be less than or equal to 140 mm Hg systolic and less than or equal to 90 mm
Hg diastolic at enrollment.

- If a person has NOT been found to have elevated blood pressure or hypertension
during screening or previously, exclude for systolic blood pressure greater than
or equal to 150 mm Hg at enrollment or diastolic blood pressure greater than or
equal to 100 mm Hg at enrollment

- Body mass index (BMI) greater than or equal to 40 or BMI greater than or equal to 35
with two or more of the following: age greater than 45, systolic blood pressure
greater than 140 mm Hg, diastolic blood pressure greater than 90 mm Hg, current
smoker, or known hyperlipidemia

- Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or
platelet disorder requiring special precautions)

- Malignancy (not excluded: a participant with a surgical excision and subsequent
observation period that in the investigator's estimation has a reasonable assurance
of sustained cure or is unlikely to recur during the period of the study)

- Seizure disorder (not excluded: a participant with a history of seizures who has not
required medications or had a seizure within the past 3 years)

- Asplenia: any condition resulting in the absence of a functional spleen

- Psychiatric condition that precludes compliance with the protocol. Specifically
excluded are participants with psychoses within the past 3 years, ongoing risk of
suicide, or history of suicide attempt or gesture within the past 3 years.

- Pregnant or breastfeeding