Evaluating the Safety and Immunogenicity of ALVAC-HIV and MF59®- or AS01B-adjuvanted Bivalent Subtype C gp120 in Healthy, HIV-uninfected Adult Participants

The primary objective of this study is to evaluate the safety and tolerability of ALVAC-HIV
and bivalent gp120 protein/MF59 or bivalent gp120 protein/AS01(B). This study will also
compare HIV-specific CD4+ T-cell response rates at the Month 6.5 timepoint (2 weeks after the
fourth vaccination) of ALVAC-HIV and bivalent gp120 protein/MF59 to each of the bivalent
gp120 protein/AS01(B) vaccine regimens. Additionally, this study will compare HIV-specific
Env-gp120 binding antibody response magnitudes at the Month 12 timepoint (6 months after the
fourth vaccination) of ALVAC-HIV and bivalent gp120 protein/MF59 to each of the bivalent
gp120 protein/AS01(B) vaccine regimens.

The study will enroll 160 healthy, HIV-uninfected volunteers aged 18 to 40 years. Groups 1 to
3 will consist of a total of 150 participants who will receive the vaccines at Months 0, 1,
3, and 6, while 10 participants in Group 4 will receive placebos at Months 0, 1, 3, 6.

Study visits will include a physical examination, an interview and/or questionnaire, HIV
testing and HIV risk-reduction counseling, and urine and blood collection. Participants may
optionally choose to provide rectal fluid, cervical fluid, semen, and/or stool samples.

Inclusion Criteria:

General and Demographic Criteria:

- Age of 18 to 40 years

- Access to a participating 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: volunteer demonstrates understanding of this study;
provides answers to a questionnaire prior to first vaccination with verbal
demonstration of understanding of all questionnaire items answered incorrectly

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

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

HIV-Related Criteria:

- Willingness to receive HIV test results

- Willingness to discuss HIV infection risks and amenable to HIV risk reduction
counseling

- Assessed by the clinic staff as being at "low risk" for HIV infection and committed to
maintaining behavior consistent with low risk of HIV exposure through the last
required protocol clinic visit (see the study protocol for more information about low
risk guidelines).

Laboratory Inclusion Values:

Hemogram/Complete Blood Count (CBC):

- Hemoglobin greater than or equal to 11.0 g/dL for volunteers who were assigned female
sex at birth, greater than or equal to 13.0 g/dL for volunteers who were assigned male
sex at birth. For transgender participants who have been on hormone therapy for more
than 6 consecutive months, determine hemoglobin eligibility based on the gender with
which they identify (ie, a transgender female who has been on hormone therapy for more
than 6 consecutive months should be assessed for eligibility using the hemoglobin
parameters for persons assigned female sex at birth).

- 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:

- Chemistry panel: ALT, AST, and ALP less than 1.25 times the institutional upper limit
of normal; creatinine less than or equal to institutional upper limit of normal.

Virology:

- Negative HIV-1 and -2 blood test: US volunteers must have a negative FDA-approved
enzyme immunoassay (EIA). Non-US 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

Urine:

- 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 cells levels within institutional normal
range).

Reproductive Status:

- Volunteers who were assigned female sex at birth: negative serum or urine beta human
chorionic gonadotropin pregnancy test performed prior to vaccination on the day of
initial vaccination. Persons who are NOT of reproductive potential due to having
undergone total hysterectomy or bilateral oophorectomy (verified by medical records),
are not required to undergo pregnancy testing.

- Reproductive status: Africa - A volunteer who was assigned female sex at birth must:

- Agree to consistently use effective contraception (see the study protocol for
more information) 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 for participants in Africa is defined as using 2 methods
of birth control. These include 1 of the following methods:

- Condoms (male or female), or

- Diaphragm or cervical cap, PLUS 1 of the following methods:

- Intrauterine device (IUD),

- Hormonal contraception (in accordance with applicable national contraception
guidelines),

- Successful vasectomy in any partner assigned male at birth (considered
successful if a volunteer reports that a male partner has [1] documentation
of azoospermia by microscopy, or [2] a vasectomy more than 2 years ago with
no resultant pregnancy despite sexual activity after vasectomy); or

- Any other contraceptive method approved by the HVTN 120 Protocol Safety
Review Team (PSRT)

- Or 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 be sexually abstinent.

- Reproductive status: United States - A volunteer who was assigned female sex at birth
must:

- Agree to consistently use effective contraception (see the study protocol for
more information) 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 for participants in the United States is defined as using
any 1 or more of the following methods of birth control:

- Condoms (male or female) with or without spermicide,

- Diaphragm or cervical cap with spermicide,

- Intrauterine device (IUD),

- Hormonal contraception, or

- Successful vasectomy in any partner assigned male at birth (considered
successful if a volunteer reports that a male partner has [1] documentation
of azoospermia by microscopy, or [2] a vasectomy more than 2 years ago with
no resultant pregnancy despite sexual activity after vasectomy); or

- Any other contraceptive method approved by the HVTN 120 PSRT

- Or must 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 must be sexually abstinent.

- Volunteers who were assigned female sex at birth 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

Other:

- Volunteers 21 years of age and older who were assigned female sex at birth consenting
to provide cervical samples:

- Pap smear within:

- the 3 years prior to enrollment with the latest result reported as normal or
ASCUS (atypical squamous cells of undetermined significance), OR

- the 5 years prior to enrollment, with the latest result reported as normal,
or ASCUS with no evidence of high risk HPV.

- If no pap smear was done within the last 3 years prior to enrollment (or within
the last 5 years, if high risk HPV testing was performed), the volunteer must be
willing to undergo a pap smear with the result reported as normal or ASCUS prior
to sample collection.

Exclusion Criteria:

General:

- 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: systolic blood pressure greater than 140 mm Hg,
diastolic blood pressure greater than 90 mm Hg, current smoker, known hyperlipidemia

- Intent to participate in another study of an investigational research agent or any
other study that requires non-HVTN HIV antibody testing during the planned duration of
the HVTN 120 study

- Pregnant or breastfeeding

- Active duty and reserve U.S. military personnel

Vaccines and Other Injections:

- HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received
control/placebo in an HIV vaccine trial, the HVTN 120 PSRT will determine eligibility
on a case-by-case basis.

- Previous receipt of monoclonal antibodies (mAbs), whether licensed or investigational;
the HVTN 120 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.
For volunteers who have received control/placebo in an experimental vaccine trial, the
HVTN 120 PSRT will determine eligibility on a case-by-case basis. For volunteers who
have received an experimental vaccine(s) more than 5 years ago, eligibility for
enrollment will be determined by the HVTN 120 PSRT on a case-by-case basis.

- Live attenuated vaccines received within 30 days before first study vaccination or
scheduled within 14 days after first study vaccination (eg, measles, mumps, and
rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever; live attenuated
influenza vaccine)

- Any vaccines that are not live attenuated vaccines and were received within 14 days
prior to first study vaccination (eg, tetanus, pneumococcal, Hepatitis A or B)

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

Immune System:

- Immunosuppressive medications received within 168 days before first study vaccination.
(Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3]
topical corticosteroids for mild, uncomplicated dermatitis; or [4] a single course of
oral/parenteral prednisone or equivalent at doses less than or equal to 60 mg/day and
length of therapy less than 11 days with completion at least 30 days prior to
enrollment.

- Serious adverse reactions to vaccines or to vaccine components such as eggs, egg
products, or neomycin, including history of anaphylaxis and related symptoms such as
hives, respiratory difficulty, angioedema, and/or abdominal pain. (Not excluded from
participation: a volunteer who had a nonanaphylactic adverse reaction to pertussis
vaccine as a child.)

- Immunoglobulin received within 60 days before first study vaccination (for mAb see
criterion above)

- Autoimmune disease

- Immunodeficiency

Clinically Significant Medical Conditions:

- 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 volunteer'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 volunteer's ability to give
informed consent

- Psychiatric condition that precludes compliance with the protocol. Specifically
excluded are persons 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. (Symptoms of asthma severity as
defined in the most recent US National Asthma Education and Prevention Program (NAEPP)
Expert Panel report). Exclude a volunteer who:

- Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or

- Uses moderate/high dose inhaled corticosteroids, or

- In the past year has either of the following:

- Greater than 1 exacerbation of symptoms treated with oral/parenteral
corticosteroids;

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

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

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

- 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 volunteers, 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.

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

- Malignancy (Not excluded from participation: Volunteer 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 volunteer
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.