Evaluating the Safety and Immune Response to Three HIV Vaccine Schedules in Healthy, HIV-Uninfected Adults

NOTE: This study has stopped enrolling new participants, and all study vaccinations for
currently enrolled participants have been stopped.

This study will evaluate the safety and immune response to three different vaccine schedules
of a DNA HIV vaccine (DNA-HIV-PT123) followed by a NYVAC HIV vaccine boost (NYVAC-HIV-PT1 and
NYVAC-HIV-PT4) in healthy, HIV-uninfected adults. Study researchers will also evaluate the
safety of administering the HIV vaccine on a shorter administration schedule.

This study will take place in two parts. Participants in Part A of the study will receive the
DNA HIV vaccine on a faster schedule than usual: at Days 0, 14, and 28. At study entry,
participants will undergo a physical examination, HIV risk reduction counseling, and
interviews and questionnaires. Female participants will take a pregnancy test. Study visits
will occur at Days 0, 14, 28, 42, 140, and 224. These study visits will include some of the
same procedures performed at study entry, as well as blood collection, urine collection, and
HIV testing.

Study researchers will evaluate participant data from Part A of the study, and if there are
no safety concerns, they will enroll participants into Part B of the study. Participants in
Part B of the study will be randomly assigned to one of three groups, and within each group,
some participants will be randomly assigned to receive placebo vaccine. Participants will
receive DNA HIV vaccine or placebo on Days 0, 14, and 28 (Group 2); or Days 0 and 28 (Group
3); or Days 0, 28, and 56 (Group 4). The NYVAC HIV vaccine boost will be administered at Day
84 (Groups 2 and 3) or 140 (Group 4). Participants in Part B of the study, in Groups 2 and 3,
will attend study visits at Days 0, 14, 28, 42, 84, 98, 168, and 273. Participants in Part B
in Group 4 will attend study visits at Days 0, 14, 28, 42, 56, 70, 140, 154, 224, and 334.
Participants in Part B of the study will undergo the same study procedures that occurred in
Part A of the study, with the addition of a cardiac symptoms assessment performed at some
study visits. Participants in Part B who received the NYVAC vaccine or its placebo prior to
study vaccinations being stopped will be contacted by phone or e-mail once a year for 5 years
after they enrolled into the study for follow-up health monitoring.

Inclusion Criteria:

- Access to a participating HIV Vaccine Trials Network (HVTN) clinical research site
(CRS) and willing 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;
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 5 years following initial study injection

- Agrees not to enroll in another study of an investigational research agent before the
last required protocol clinic visit

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

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

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

- White blood cell count equal to 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

- Platelets equal to 125,000 to 550,000/mm^3

- Chemistry panel: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and
alkaline phosphatase less than 1.25 times the institutional upper limit of normal
(IULN); creatinine less than 1.1 times the IULN

- Negative HIV-1 and -2 blood test: Participants in the United States must have a
negative Food and Drug Administration (FDA)-approved enzyme immunoassay. Non-U.S.
sites may use locally available assays that have been approved by HVTN Laboratory
Operations.

- Negative hepatitis B surface antigen (HBsAg)

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

- Normal urine: Negative urine glucose and negative or trace urine protein, and negative
or trace urine hemoglobin (if trace hemoglobin is present on dipstick, a microscopic
urinalysis with red blood cell levels within institutional normal range)

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

- Reproductive status: Participants who were born female must 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. More
information on this criterion can be found in the protocol.

- 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:

- Untreated or incompletely treated syphilis infection

- HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received
control/placebo in an HIV vaccine trial, the HVTN 092 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 volunteers who have received control/placebo in an experimental
vaccine trial, the HVTN 092 PSRT will determine eligibility on a case-by-case basis.
For volunteers who have received an experimental vaccine(s) greater than 5 years ago,
eligibility for enrollment will be determined by the HVTN 092 PSRT on a case-by-case
basis.

- Immunosuppressive medications received within 168 days before first vaccination. (Not
excluded: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical
corticosteroids for mild, uncomplicated dermatitis; or [4] a single course of
oral/parenteral corticosteroids at doses less than 2 mg/kg/day and length of therapy
less than 11 days 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 before the
last required protocol clinic visit

- 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 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. More information on this criterion can be
found in the protocol.

- 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:
participants 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)

- Participants who have two or more of the following cardiac risk factors: (1)
participant report of history of elevated blood cholesterol defined as fasting
low-density lipoprotein (LDL) greater than 160 mg/dL; (2) first degree relative (e.g.,
mother, father, brother, or sister) who had coronary artery disease before the age of
50 years); (3) current smoker; or (4) body mass index (BMI) greater than or equal to
35

- Electrocardiogram (ECG) with clinically significant findings, or features that would
interfere with the assessment of myo/pericarditis, as determined by the contract ECG
lab, cardiologist, or study clinician. More information on this criterion can be found
in the protocol.

- Autoimmune disease. (Not excluded: mild, well-controlled psoriasis.)

- Immunodeficiency

- Asthma other than mild, well-controlled asthma. More information on this criterion can
be found in the protocol.

- 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 Hg systolic and less than or equal to 90 mm Hg diastolic, with or
without medication, with only isolated, brief instances of higher readings, which 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.

- BMI greater than or equal to 40; less than or equal to 18; 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: participant who has had malignancy excised surgically and
who, in the investigator's estimation, has a reasonable assurance of sustained cure,
or who is unlikely to experience recurrence of malignancy during the period of the
study.)

- Seizure disorder: History of seizure(s) within past 3 years. Also exclude if
participant has used medications in order to prevent or treat seizure(s) at any time
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 people with psychoses within the past 3 years, ongoing risk for suicide,
or history of suicide attempt or gesture within the past 3 years.

- Pregnant or breastfeeding