Evaluating the Safety and Immune Response to Two HIV Vaccine Regimens in Healthy, HIV-Uninfected Adults in the United States and South Africa

This study will evaluate the safety, tolerability, and immune response to two different
vaccine schedules of a prime with either DNA HIV vaccine (DNA-HIV-PT123), or NYVAC HIV
vaccine (NYVAC-HIV-PT1 and NYVAC-HIV-PT4) followed by a boost combination of NYVAC HIV
vaccine (PT1 & PT4) and AIDSVAX B/E. Study researchers will also evaluate whether body mass
index (BMI) and/or sex impact the immunogenicity of the vaccine regimens in participants
from South Africa, and look at regional differences in immunologic responses between United
States and South African participants.

The study will enroll 264 healthy, HIV-uninfected people, ages 18-50, in the United States
and South Africa.

Participants will be randomly assigned to one of three groups and receive either one of the
vaccine regimens or placebo. Participants will receive injections according to their
assigned group schedule at study entry (Month 0) and Months 1, 3, and 6.

Participants will remain in the clinic for 30 minutes after receiving the vaccines for
observation and monitoring. For 7 days after receiving the vaccines, participants will
record their symptoms and report them to study researchers.

Study visits will occur at study entry, and Months 1, 1.5, 3, 3.5, 6, 6.5, 9, and 12. All
study visits will include a physical examination, HIV risk reduction counseling, and
interviews and/or questionnaires. Select study visits will include urine collection, an
electrocardiogram (ECG), blood collection, a pregnancy test for female participants, and HIV
testing. At some visits, some participants may also provide samples of cervical fluid,
rectal fluid, and/or semen. Study researchers will contact participants by telephone or
e-mail once a year for 3 years following the first vaccination for follow-up health
monitoring.

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;
completes a questionnaire prior to first vaccination with verbal demonstration of
understanding of all questionnaire items answered incorrectly

- 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 before the
last required protocol clinic visit

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

- 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

- 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 or equal to 1.1 times the IULN

- Cardiac Troponin T or I (cTnT or cTnI) does not exceed the IULN

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

1. Negative urine glucose, and

2. Negative or trace urine protein, and

3. Negative or trace urine hemoglobin (if trace hemoglobin is present on dipstick,
a microscopic urinalysis with red blood cells levels within institutional normal
range).

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

- Reproductive status: a participant who was 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:

- Blood products received within 120 days before first vaccination

- Investigational research agents received within 30 days before first vaccination

- Body mass index (BMI) greater than or equal to 40; or BMI greater than or equal to 35
with 2 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, or known
hyperlipidemia

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

- Pregnant or breastfeeding

- HIV vaccine(s) received in a prior HIV vaccine trial. For participants who have
received control/placebo in an HIV vaccine trial, the HVTN 101 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 or (South Africa) Medicines Control Council (MCC). For participants who
have received control/placebo in an experimental vaccine trial, the HVTN 101 PSRT
will determine eligibility on a case-by-case basis. For participants who have
received an experimental vaccine(s) greater than 5 years ago, eligibility for
enrollment will be determined by the HVTN 101 PSRT on a case-by-case basis.

- 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)

- 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

- 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.)

- 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.)

- Immunoglobulin received within 60 days before first vaccination

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

- Immunodeficiency

- Untreated or incompletely treated syphilis infection

- 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

- 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.

- Current anti-tuberculosis (TB) prophylaxis or therapy

- 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

- Hypertension:

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

2. 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.

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

- 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.

- Participants who have 2 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) BMI greater than or equal to 35

- Allergy to eggs or egg products

- 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

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